{"gene":"FKBP5","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":1993,"finding":"FKBP5 (FKBP54) was identified as a novel FK506-binding immunophilin that co-purifies with avian progesterone receptor complexes. It binds FK506 affinity resin and exists predominantly in oligomeric complexes at low ionic strength, distinct from FKBP52 (p50).","method":"FK506 affinity chromatography, glycerol density gradient sedimentation, immunoprecipitation with anti-p54 antibody","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical purification and affinity chromatography from native complexes, single lab but multiple orthogonal methods","pmids":["7693698"],"is_preprint":false},{"year":1997,"finding":"Human FKBP51 (encoded by FKBP5) mediates FK506-dependent inhibition of calcineurin phosphatase activity in vitro, is induced by glucocorticoids in human T cells, and is abundantly expressed across numerous human tissues.","method":"In vitro calcineurin phosphatase inhibition assay, Western blot of 17 human tissues, glucocorticoid induction in C7TK.4 cells","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — in vitro enzymatic assay with protein purification, multiple tissues and cell lines, single lab","pmids":["9125197"],"is_preprint":false},{"year":2002,"finding":"FKBP51 interacts directly with calcineurin in a manner that is independent of FK506, calcium, and calmodulin. The C-terminal domain (TPR domain) of FKBP51, not the FK1 (PPIase) domain, is required for calcineurin binding. Unlike FKBP12, FKBP51 overexpression did not significantly affect NFAT-driven transcription.","method":"GST pulldown with purified calcineurin and T cell lysates, calmodulin-Sepharose co-precipitation, FKBP51 deletion mutants, NFAT reporter assay in Jurkat T cells","journal":"Journal of cellular biochemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — reconstituted pulldown with purified proteins, domain mapping by deletion mutagenesis, functional reporter assay; multiple orthogonal methods in single study","pmids":["11813252"],"is_preprint":false},{"year":2009,"finding":"FKBP51 acts as an Hsp90 co-chaperone in the glucocorticoid receptor (GR) complex; when bound, cortisol affinity for GR is reduced and nuclear translocation is less efficient. FKBP5 mRNA and protein are induced by GR activation via intronic hormone response elements, forming an ultra-short negative feedback loop for GR sensitivity.","method":"Pharmacological and molecular characterization of GR-chaperone complexes; GR sensitivity and cortisol-binding assays; FKBP5 induction experiments with glucocorticoids","journal":"Psychoneuroendocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Strong — well-replicated mechanistic model from multiple labs; review synthesizing experimental data; mechanism established in original biochemical studies cited within","pmids":["19560279"],"is_preprint":false},{"year":2011,"finding":"FKBP51 associates with GSK3β mainly through its FK1 domain and increases phosphorylation of GSK3β at serine 9 (inhibitory phosphorylation). FKBP51 also associates with PP2A and CDK5 within the GSK3β heterocomplex, and acts through GSK3β on downstream targets Tau, β-catenin, and TCF/LEF. Deletion of FKBP51 blunted lithium- or paroxetine-induced pGSK3β(S9) increase in cells and mice.","method":"Co-immunoprecipitation, reporter gene assays, protein association analyses, FKBP51 knockout mouse experiments, domain mapping (FK1 domain)","journal":"Molecular psychiatry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, domain mapping, KO mouse validation, multiple downstream readouts in single study","pmids":["25849320"],"is_preprint":false},{"year":2011,"finding":"FKBP51 knockout mice show antidepressant-like behavior with reduced post-stress corticosterone levels and modulated age-dependent anxiety, demonstrating that FKBP51 regulates HPA axis stress reactivity in vivo.","method":"FKBP5 knockout mouse model, behavioral assays (forced swim, elevated plus maze), corticosterone measurements","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO with defined behavioral and neuroendocrine phenotype, single lab","pmids":["21935478"],"is_preprint":false},{"year":2012,"finding":"A functional FKBP5 polymorphism (rs1360780) alters chromatin interaction between the transcription start site and long-range enhancers, enabling allele-specific, childhood trauma-dependent DNA demethylation at glucocorticoid response elements in FKBP5 introns. This demethylation increases stress-dependent FKBP5 transcription and dysregulates the HPA axis.","method":"Chromatin conformation capture (3C), bisulfite sequencing of GRE CpG sites, allele-specific expression analysis, cortisol/ACTH measurements in human cohorts and cell lines","journal":"Nature neuroscience","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — chromatin conformation capture, allele-specific methylation quantification, functional expression assays; replicated in human cohorts and cellular models","pmids":["23201972"],"is_preprint":false},{"year":2014,"finding":"FKBP51 reciprocally regulates GRα and PPARγ via the Akt-p38 kinase pathway. FKBP51 acts as an essential chaperone to the Akt-specific phosphatase PHLPP, thereby suppressing Akt and downstream p38 kinase activity. Loss of FKBP51 increases phosphorylation of PPARγ at S112 (inhibitory) and GRα at S220/S234 (activating), and shifts both receptors to the nucleus.","method":"FKBP51 knockout (51KO) MEFs, overexpression in COS-7 cells, reporter gene assays, western blotting for phosphorylation, p38 kinase inhibitor (PD169316), subcellular fractionation","journal":"Molecular endocrinology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — KO MEFs with rescue, pharmacological inhibition, phospho-site mapping, multiple orthogonal methods in single study","pmids":["24933248"],"is_preprint":false},{"year":2014,"finding":"FKBP51 is a required regulator of adipogenesis: FKBP51 KO MEFs show near-complete resistance to differentiation with reduced lipid accumulation, reduced PPARγ activity, elevated GRα transrepression, and reduced fatty acid synthase activity. Rescue by re-expression of FKBP51 confirmed specificity. The S112A PPARγ and triple S212A/S220A/S234A GRα mutants partially restored lipid accumulation in KO cells, identifying these phospho-residues as targets of the FKBP51/p38 axis.","method":"3T3-L1 FKBP51 knockdown, 51KO MEFs with FKBP51 re-expression rescue, adipogenic gene expression, fatty acid synthase activity, p38 inhibitor, phospho-site mutants","journal":"Molecular endocrinology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — KO with genetic rescue, phospho-site mutagenesis, multiple functional assays; mechanistic detail for specific residues","pmids":["24933247"],"is_preprint":false},{"year":2015,"finding":"FKBP51 associates with BECN1 (Beclin-1), alters its phosphorylation and protein levels, and enhances autophagy markers and autophagic flux. The autophagy-enhancing function of FKBP51 is required for antidepressant action in cells and mice.","method":"Co-immunoprecipitation of FKBP51-BECN1, western blot for autophagy markers (LC3-II), autophagic flux assays, FKBP5 KO mice, antidepressant behavioral testing","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, autophagic flux assay, KO mouse behavioral validation; single lab","pmids":["25714272"],"is_preprint":false},{"year":2017,"finding":"FKBP51 acts as a scaffolding protein enhancing PHLPP-AKT interaction to facilitate PHLPP-mediated dephosphorylation of AKT at Ser473, thereby negatively regulating AKT activation in cancer cells.","method":"Co-immunoprecipitation, western blot for AKT phosphorylation, FKBP51 overexpression/knockdown, pancreatic cancer cell lines","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP establishing ternary complex, phosphorylation assay, single lab","pmids":["28363942"],"is_preprint":false},{"year":2017,"finding":"USP49 deubiquitinates and stabilizes FKBP51, which in turn enhances PHLPP-mediated dephosphorylation of AKT, establishing USP49 as an upstream regulator of the FKBP51-PHLPP-AKT pathway.","method":"Co-immunoprecipitation, ubiquitination assay, western blot for FKBP51 protein stability and AKT phosphorylation, USP49 overexpression/knockdown in pancreatic cancer cells","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, functional rescue; single lab","pmids":["28363942"],"is_preprint":false},{"year":2017,"finding":"FKBP51 plays a role in energy and glucose homeostasis: FKBP51 associates with AS160 (a substrate of AKT2 involved in glucose uptake), and FKBP51 antagonism increases phosphorylation of AS160, increases GLUT4 expression at the plasma membrane, and enhances glucose uptake in skeletal myotubes. Fkbp5 KO mice are protected from high-fat diet-induced weight gain and show improved glucose tolerance.","method":"Co-immunoprecipitation (FKBP51-AS160), GLUT4 membrane fractionation, glucose uptake assay in myotubes, Fkbp5 KO mouse model, pharmacological inhibition with SAFit2","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP, subcellular fractionation, in vitro functional assay, KO mouse, pharmacological validation; multiple orthogonal methods","pmids":["29170369"],"is_preprint":false},{"year":2017,"finding":"FKBP51 interacts with DLC1 and DLC2 (Rho GTPase-activating proteins). Overexpression of FKBP51 enhances RhoA activity and Rho-ROCK signaling, promoting cell motility and invasion, while FKBP51 depletion reduces RhoA activity and causes cortical actin redistribution.","method":"Immunoprecipitation and mass spectrometry (interactor identification), RhoA activity assay, cell motility/invasion assays, FKBP51 overexpression and knockdown in U2OS cells","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — IP-MS for interactor discovery, RhoA activity assay, functional invasion assay; single lab","pmids":["28032931"],"is_preprint":false},{"year":2018,"finding":"FKBP51 modulates NF-κB signaling: FKBP51 is present in a complex comprising Hsp90, GR, and members of the IKK family (IKKα/β). FKBP51 silencing reduces NF-κB (p50/p65) nuclear translocation, decreases ICAM expression and cytokine/chemokine secretion, and increases GR sensitivity to glucocorticoids in bronchial epithelial cells.","method":"Co-immunoprecipitation (anti-FKBP51 antibody), siRNA silencing, NF-κB nuclear translocation assay, cytokine ELISA, GR reporter assay, FKBP51 overexpression in murine pulmonary inflammation model","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP establishing Hsp90/GR/IKK complex, functional knockdown with multiple readouts; single lab","pmids":["30169894"],"is_preprint":false},{"year":2018,"finding":"FKBP51 silencing reduces NF-κB signaling and increases GR sensitivity, identifying FKBP51 as a component of the IKK complex that regulates both NF-κB-driven inflammation and glucocorticoid responsiveness.","method":"Immunoprecipitation, siRNA, reporter assay, cytokine measurements","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and functional silencing, single lab","pmids":["30169894"],"is_preprint":false},{"year":2020,"finding":"The glucocorticoid receptor (GR) and FKBP51 form a protein complex that is elevated in PTSD patients and in fear-conditioned mice. The GR-FKBP51 complex is associated with decreased GR phosphorylation, decreased nuclear GR, and lower 14-3-3ε expression. A peptide disrupting GR-FKBP51 binding reverses fear conditioning-induced behavioral and molecular changes, including restoring GR phosphorylation, increasing GR-FKBP52 interaction, and promoting GR nuclear translocation.","method":"Co-immunoprecipitation in human blood samples and mouse brain tissue, GR phosphorylation western blot, nuclear GR fractionation, peptide-mediated disruption of GR-FKBP51 complex, fear conditioning behavioral assay","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP in human and mouse samples, mechanistic peptide disruption, multiple molecular readouts validated in vivo","pmids":["31929189"],"is_preprint":false},{"year":2020,"finding":"USP53 deubiquitinates FKBP51, leading to dephosphorylation of AKT1 and inhibition of tumor growth in lung adenocarcinoma, establishing USP53 as another deubiquitinase regulating FKBP51 stability and thus the AKT pathway.","method":"Co-immunoprecipitation, ubiquitination assay, western blot for AKT phosphorylation, USP53 overexpression/knockdown, in vivo xenograft model","journal":"Molecular carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, in vivo tumor model; single lab","pmids":["32511815"],"is_preprint":false},{"year":2020,"finding":"FKBP5 binds IKKα, which is critical for RIG-I-induced innate immune responses. FKBP5 knockout increases influenza A virus (IAV) infection, demonstrating FKBP5 as a host restriction factor acting through RIG-I-mediated NF-κB signaling.","method":"FKBP5 KO cells, Co-immunoprecipitation (FKBP5-IKKα), viral infection assay, NF-κB reporter, ISG expression assay","journal":"Viruses","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, KO with functional viral phenotype, NF-κB reporter; single lab","pmids":["32580383"],"is_preprint":false},{"year":2021,"finding":"Mineralocorticoid receptor (MR) binding to the Fkbp5 gene (rather than GR binding) regulates baseline FKBP5 expression in hippocampal neurons. MR-dependent FKBP5 expression modifies GR sensitivity to glucocorticoids. Pharmacological MR inhibition and region-specific MR deletion reduce hippocampal Fkbp5 levels and dampen stress-induced glucocorticoid increase.","method":"Biotinylated-oligonucleotide immunoprecipitation (biotin-oligo-IP) in primary hippocampal neurons, pharmacological MR antagonism, conditional MR knockout mice, corticosterone measurements","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct MR-DNA binding assay, conditional KO mouse, pharmacological validation; multiple orthogonal methods in single study","pmids":["34077736"],"is_preprint":false},{"year":2021,"finding":"FKBP5 interacts and colocalizes with HTT (huntingtin) in mouse striatum and cortex. Decreasing FKBP5 levels or activity reduces mutant HTT via increased LC3-II levels and macroautophagic flux, in an MTOR-independent manner. In vivo SAFit2 treatment reduces HTT levels in HD mouse models.","method":"Co-immunoprecipitation (FKBP5-HTT), siRNA knockdown, SAFit2 pharmacological inhibition, LC3-II western blot, autophagy flux assay, in vivo mouse models (R6/2, zQ175)","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP establishing interaction, genetic and pharmacological loss-of-function, in vivo validation in two mouse models","pmids":["34024231"],"is_preprint":false},{"year":2021,"finding":"FKBP51 promotes decidualization of human endometrial stromal cells (ESCs) by reducing Ser473 phosphorylation of AKT, which increases FOXO1A expression. FKBP51 shRNA inhibited decidualization markers (IGFBP1, PRL) and was rescued by FKBP51 cDNA re-expression.","method":"shRNA knockdown of FKBP51 in primary human ESCs, western blot for p-AKT(S473), RT-PCR for IGFBP1/PRL, AKT activator SC79, cDNA rescue, immunohistochemistry on endometrial tissue microarray","journal":"Reproduction","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD with rescue, AKT phosphorylation assay, functional decidualization markers; single lab","pmids":["29363568"],"is_preprint":false},{"year":2021,"finding":"FKBP51 binding to progesterone receptor (PR) inhibits PR function. Maternal stress increases uterine FKBP51 expression and nuclear FKBP51-PR binding in decidual cells, causing functional P4 withdrawal and preterm birth. Fkbp5-/- mice are completely resistant to maternal stress-induced preterm birth.","method":"Co-immunoprecipitation (FKBP51-PR), Fkbp5 KO mouse model, maternal restraint stress paradigm, gene expression analysis (PR, AKR1C18, Oxtr), immunohistochemistry on human decidua from preterm birth cases","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP, Fkbp5 KO mouse with complete phenotypic rescue, human tissue validation, multiple molecular readouts","pmids":["33836562"],"is_preprint":false},{"year":2021,"finding":"FKBP5 regulates trophoblast function and macrophage polarization via PI3K/AKT signaling (trophoblast) and ROS/NF-κB signaling (macrophages). FKBP5 inhibits HAPLN1 expression through suppression of PI3K/AKT and inhibits trophoblast IL-6 secretion, promoting M1 macrophage polarization. FKBP5 inhibitors improved embryo resorption rate in a mouse miscarriage model.","method":"Overexpression/knockdown in trophoblast cell lines and THP-1-derived macrophages, western blot for PI3K/AKT and NF-κB pathway components, cytokine ELISA, mouse miscarriage model with FKBP5 inhibitor","journal":"Free radical biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss/gain-of-function with pathway readouts, in vivo mouse model; single lab","pmids":["37827456"],"is_preprint":false},{"year":2021,"finding":"Loss of FKBP5 in hippocampal neurons reduces long-term potentiation (LTP), decreases excitatory synaptic activity (reduced mEPSC frequency, reduced NMDAR1, NMDAR2B, and AMPAR expression), and increases inhibitory GABAergic signaling (elevated GABA, GAD65 expression, increased mIPSC frequency).","method":"Fkbp5 KO mice, electrophysiology (LTP recording, mEPSC, mIPSC), western blot for glutamate and GABA receptor subunits and synthesis enzymes","journal":"Neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse with electrophysiological and biochemical phenotyping; single lab","pmids":["30685540"],"is_preprint":false},{"year":2021,"finding":"FKBP51 is phosphorylated, SUMOylated, and acetylated as post-translational modifications that regulate its scaffolding interactions. SUMOylation is required for FKBP51's inhibitory action on GR.","method":"Review of biochemical studies including in vitro SUMOylation, Ni2+ affinity pulldown, site-directed mutagenesis from primary literature","journal":"Biochemical Society transactions","confidence":"Low","confidence_rationale":"Tier 3 / Weak — review paper synthesizing PTM data; specific SUMO requirement supported by subsequent experimental work (PMID 35256747)","pmids":["31754722"],"is_preprint":false},{"year":2022,"finding":"Tricyclic antidepressants (particularly clomipramine) inhibit FKBP51 SUMOylation by binding to FKBP51 and preventing its interaction with the SUMO E3 ligase PIAS4. Inhibition of FKBP51 SUMOylation decreases FKBP51 binding to Hsp90 and GR, facilitates FKBP52 recruitment to the GR complex, and enhances GR transcriptional activity.","method":"Ni2+ affinity pulldown screening, in vitro SUMOylation assay, co-immunoprecipitation (FKBP51-PIAS4, FKBP51-GR), PIAS4 siRNA in rat primary astrocytes, in vivo clomipramine treatment in mice","journal":"Molecular psychiatry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro SUMOylation assay, Co-IP for complex changes, siRNA functional rescue, in vivo mouse validation; multiple orthogonal methods","pmids":["35256747"],"is_preprint":false},{"year":2022,"finding":"FKBP51 serves as a central scaffold in the mediobasal hypothalamus (MBH) linking the LKB1/AMPK complex to WIPI4 and TSC2 to WIPI3, thereby regulating the balance between autophagy and mTOR signaling in response to metabolic challenges. MBH-specific FKBP51 deletion induces obesity; overexpression protects against high-fat diet-induced obesity.","method":"Mass spectrometry-based metabolomics (FKBP51 KO cells), co-immunoprecipitation (FKBP51-LKB1/AMPK-WIPI4; TSC2-WIPI3), stereotaxic viral MBH-specific KO/overexpression, high-fat diet mouse model","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP defining multiprotein complexes, region-specific genetic manipulation, metabolic phenotyping; multiple orthogonal methods in a single rigorous study","pmids":["35263141"],"is_preprint":false},{"year":2021,"finding":"FKBP51 regulates androgen receptor (AR) dimer formation; depletion of FKBP51 reduces AR dimer formation, chromatin binding, and phosphorylation. The PPIase (FK1 domain) activity of FKBP51 is required for AR dimerization and prostate cancer cell growth.","method":"FKBP51 depletion by siRNA/shRNA, AR dimerization assay, chromatin immunoprecipitation, cell proliferation assay, FK1 domain inhibitor (FK506), PPIase activity requirement tested with domain mutants","journal":"Molecular oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with multiple molecular readouts, domain inhibitor; single lab","pmids":["34057812"],"is_preprint":false},{"year":2022,"finding":"FKBP51 reduces the stability of ERα (estrogen receptor alpha) in breast cancer cells, reciprocal to FKBP52 which stabilizes ERα. FKBP51 was more abundantly expressed in normal tissues than cancer cells.","method":"FKBP51/FKBP52 depletion in breast cancer cell lines, ERα protein stability assay, western blot, co-immunoprecipitation, proliferation assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD with protein stability readout, reciprocal functional comparison; single lab","pmids":["35394865"],"is_preprint":false},{"year":2023,"finding":"FKBP5 facilitates assembly of the IκB kinase (IKK) complex for NF-κB activation. CBD (cannabidiol) directly binds FKBP5 at tyrosine 113 (Y113), stabilizes it, and inhibits IKK complex assembly and NF-κB activation. Y113A mutation of FKBP5 reduces CBD's anti-inflammatory effect.","method":"Protein intrinsic fluorescence titration, cellular thermal shift assay (CETSA), Stern-Volmer analysis, protein thermal shift assay, Y113A site-directed mutagenesis, IKK complex Co-IP, NF-κB reporter assay, cytokine measurements, in vivo CCI pain model","journal":"Brain, behavior, and immunity","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct binding assay, CETSA target engagement, active-site mutagenesis (Y113A), functional complex assembly assay, in vivo validation","pmids":["37196785"],"is_preprint":false},{"year":2023,"finding":"FKBP5 negatively modulates HIF-1α protein levels in cardiomyocytes by competitively interacting with Hsp90, thereby suppressing NCX1 (Na+/Ca2+-exchanger 1) transcription and preventing atrial arrhythmogenesis. Cardiomyocyte-specific FKBP5 knockdown increases HIF-1α, NCX1, action potential alternans, and spontaneous Ca2+ waves.","method":"Cardiomyocyte-specific Fkbp5 knockdown mouse (Myh6-Cre), echocardiography, intracardiac stimulation, optical mapping, patch-clamp electrophysiology, Co-immunoprecipitation (FKBP5-Hsp90-HIF-1α), Hsp90 inhibitor (17-AAG) rescue","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with electrophysiological phenotype, Co-IP, pharmacological rescue, human atrial tissue validation; multiple orthogonal methods","pmids":["37154033"],"is_preprint":false},{"year":2023,"finding":"FKBP5 regulates FOXO1 phosphorylation at Serine 256 in pancreatic β-cells. FKBP5 inhibition (siRNA or SAFit2) under inflammatory stress promotes β-cell survival, improves insulin secretion, and upregulates MAFA and NKX6.1. Silencing of FOXO1 abolishes the protective effect of FKBP5 inhibition.","method":"siRNA knockdown, SAFit2 pharmacological inhibition, western blot for FOXO1-pS256 and AKT signaling, insulin secretion assay, FOXO1 siRNA epistasis, human and mouse primary islets","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis experiment (FOXO1 KD reversal), phospho-site western blot, primary human islet validation; single lab","pmids":["37452039"],"is_preprint":false},{"year":2023,"finding":"FKBP5 activates mitophagy in oligodendrocytes by ablating PPAR-γ, shaping the remyelination environment. FKBP5 protein levels are elevated in the CNS of cuprizone-treated demyelinated mice and regulate PINK1/Parkin-mediated mitophagy through PPAR-γ.","method":"Fkbp5 knockout mice in cuprizone demyelination model, PPAR-γ expression analysis, mitophagy assay (PINK1/Parkin pathway markers), western blot, histology","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse with functional phenotype, pathway marker analysis; single lab","pmids":["37952053"],"is_preprint":false},{"year":2023,"finding":"SIRT1 deacetylates FKBP5 in the BNST, inducing FKBP5 dissociation from the GR, which enhances GR-mediated CRF transcriptional repression and reduces anxiety. SIRT1 directly interacts with and deacetylates FKBP5 as part of this anxiolytic mechanism.","method":"Co-immunoprecipitation (SIRT1-FKBP5-GR), site-specific in vivo manipulations (SIRT1 overexpression/pharmacological activation in BNST), CRF expression, electrophysiology, MiniScope calcium imaging, mass spectroscopy","journal":"Molecular psychiatry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, in vivo cell-type-specific manipulation, multiple molecular and behavioral readouts; single lab","pmids":["37386058"],"is_preprint":false},{"year":2023,"finding":"FKBP5 levels are inversely correlated with dendritic mushroom spine density and BDNF levels in superficial layer excitatory neurons of the human neocortex (BA11), suggesting FKBP5 impacts synaptic plasticity in a cell-type-specific manner.","method":"Single-nucleus RNA sequencing, bulk RNA sequencing, RNAscope, immunohistochemistry, western blot (postmortem human brain n=1024); dendritic spine density measurement","journal":"Acta neuropathologica","confidence":"Low","confidence_rationale":"Tier 3 / Weak — correlational finding in postmortem tissue; no experimental manipulation of FKBP5 to demonstrate causal mechanism","pmids":["36729133"],"is_preprint":false},{"year":2024,"finding":"SKA2 promotes GR signaling by enhancing GR-FKBP4 (FKBP52) interaction, which leads to dissociation of FKBP51 from the GR complex. This mechanism was demonstrated in neurons; SKA2 in CRH+ neurons of the hypothalamic PVN is required for HPA axis responsiveness and negative feedback.","method":"In vitro cell-based co-immunoprecipitation assays, conditional neuron-specific SKA2 manipulation (Crh+ neurons), HPA axis responsiveness (corticosterone measurements), postmortem human brain expression","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP establishing GR-FKBP4-FKBP5 complex remodeling, conditional in vivo neuronal manipulation; single lab","pmids":["39705315"],"is_preprint":false},{"year":2017,"finding":"A V55L missense mutation in FKBP51 enhances AKT phosphorylation and kinase activity. Knock-in mice carrying FKBP51(V55L) show hyperresponsive osteoclast precursors to RANKL, increased osteoclast bone resorption activity, and increased trabecular bone resorption, linked to elevated AKT phosphorylation in bone marrow-derived macrophages.","method":"Whole-exome sequencing (mutation identification), FKBP51V55L knock-in transgenic mice, RANKL-stimulated osteoclast differentiation assay, bone resorption assay, western blot for AKT phosphorylation, micro-CT analysis","journal":"Experimental & molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function knock-in mice, functional osteoclast assays, AKT pathway readout; single lab","pmids":["28524179"],"is_preprint":false},{"year":2021,"finding":"Fkbp4 (FKBP52) and Fkbp5 (FKBP51) differentially regulate GR nuclear translocation and dynein interaction. In pituitary corticotroph cells, Fkbp5 knockdown further decreases Pomc mRNA levels (i.e., FKBP5 reduces efficiency of glucocorticoid-mediated Pomc suppression), while Fkbp4 knockdown partially cancels dexamethasone-induced Pomc decrease.","method":"siRNA knockdown of Fkbp4 and Fkbp5 in AtT-20 corticotroph cells, RT-PCR for Pomc mRNA, western blot for FKBP4/5 protein, dexamethasone treatment","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA epistasis in cell line showing opposing functions of FKBP4 vs FKBP5; single lab","pmids":["34072036"],"is_preprint":false}],"current_model":"FKBP51 (encoded by FKBP5) is an Hsp90/Hsp70 co-chaperone and scaffolding immunophilin that acts as a central negative regulator of glucocorticoid receptor (GR) sensitivity by binding the GR-Hsp90 heterocomplex to reduce cortisol affinity and impair nuclear translocation; it is itself transcriptionally induced by GR activation at intronic glucocorticoid response elements (creating an ultra-short negative feedback loop subject to allele-specific, trauma-dependent DNA demethylation), and it regulates multiple additional signaling hubs including the PHLPP-AKT axis (as a scaffold facilitating AKT dephosphorylation), the Akt-p38-PPARγ/GRα phosphorylation axis controlling adipogenesis, GSK3β inhibitory phosphorylation, the IKK/NF-κB complex assembly, Beclin-1-dependent autophagy, WIPI/LKB1-AMPK/mTOR metabolic sensing in the hypothalamus, RhoA-ROCK-mediated cell motility, HIF-1α stability in cardiomyocytes, and androgen receptor dimerization; its activity is regulated post-translationally by SUMOylation (required for GR inhibition, targeted by tricyclic antidepressants via PIAS4), deacetylation by SIRT1, and protein stabilization by deubiquitinases USP49 and USP53."},"narrative":{"mechanistic_narrative":"FKBP51 (encoded by FKBP5) is an FK506-binding immunophilin that functions principally as an Hsp90 co-chaperone and scaffold controlling steroid hormone receptor signaling and stress physiology [PMID:7693698, PMID:19560279]. Originally identified as a peptidyl-prolyl isomerase co-purifying with progesterone receptor complexes [PMID:7693698], it binds the glucocorticoid receptor (GR)-Hsp90 heterocomplex through its TPR domain, reducing cortisol affinity and impairing GR nuclear translocation [PMID:19560279, PMID:31929189]; because FKBP5 is itself transcriptionally induced by activated GR via intronic hormone response elements, it forms an ultra-short negative feedback loop tuning GR sensitivity [PMID:19560279], and baseline expression is set by mineralocorticoid receptor binding to the gene [PMID:34077736]. This GR-restraining activity governs HPA-axis stress reactivity in vivo, with Fkbp5 knockout producing antidepressant-like, stress-resistant phenotypes [PMID:21935478], and a regulatory rs1360780 polymorphism enabling trauma-dependent demethylation of intronic GREs that elevates stress-induced FKBP5 and dysregulates the HPA axis [PMID:23201972]. FKBP51 also acts reciprocally on other receptors, inhibiting progesterone receptor in decidual cells where maternal-stress-induced FKBP51-PR binding drives preterm birth [PMID:33836562], and controlling androgen and estrogen receptor function [PMID:34057812, PMID:35394865]. Beyond steroid receptors, FKBP51 is a broad signaling scaffold: it chaperones the AKT phosphatase PHLPP to promote AKT(Ser473) dephosphorylation [PMID:28363942], thereby controlling an Akt-p38-PPARγ/GRα axis required for adipogenesis [PMID:24933248, PMID:24933247] and influencing glucose homeostasis through AS160/GLUT4 [PMID:29170369] and FOXO1 in β-cells [PMID:37452039]; it scaffolds GSK3β inhibitory phosphorylation [PMID:25849320], assembles the IKK complex to drive NF-κB-dependent inflammation and innate antiviral responses [PMID:30169894, PMID:32580383, PMID:37196785], promotes Beclin-1- and HTT-related autophagy [PMID:25714272, PMID:34024231], and links LKB1/AMPK-WIPI and TSC2-WIPI complexes to balance hypothalamic autophagy and mTOR signaling and body weight [PMID:35263141]. FKBP51 scaffolding is regulated post-translationally: SUMOylation via PIAS4 is required for its GR-inhibitory action and is blocked by tricyclic antidepressants [PMID:35256747], SIRT1 deacetylation dissociates it from GR [PMID:37386058], and deubiquitinases USP49 and USP53 stabilize it to sustain the PHLPP-AKT axis [PMID:28363942, PMID:32511815].","teleology":[{"year":1993,"claim":"Establishing FKBP5 as a distinct immunophilin associated with steroid receptor complexes defined its founding biochemical identity.","evidence":"FK506 affinity chromatography and density-gradient analysis of avian progesterone receptor complexes","pmids":["7693698"],"confidence":"Medium","gaps":["No functional consequence of receptor association defined","Human ortholog and physiology not yet addressed"]},{"year":1997,"claim":"Human FKBP51 was shown to inhibit calcineurin in an FK506-dependent manner and to be glucocorticoid-inducible, linking it to immune signaling and steroid responsiveness.","evidence":"In vitro calcineurin phosphatase assays, multi-tissue Western blots, and glucocorticoid induction in human T cells","pmids":["9125197"],"confidence":"Medium","gaps":["Mechanism of induction not mapped","Physiological relevance of calcineurin inhibition unclear"]},{"year":2002,"claim":"Domain mapping showed FKBP51 binds calcineurin through its TPR domain independently of FK506/calcium, distinguishing its mode of interaction from FKBP12 and clarifying that it does not regulate NFAT like FKBP12.","evidence":"GST pulldowns with purified proteins, deletion-mutant domain mapping, NFAT reporter assays in Jurkat cells","pmids":["11813252"],"confidence":"High","gaps":["In vivo significance of calcineurin binding not demonstrated","Did not address GR-complex role"]},{"year":2009,"claim":"FKBP51 was defined as an Hsp90 co-chaperone that reduces GR cortisol affinity and nuclear translocation, and is induced by GR via intronic response elements, establishing the ultra-short negative feedback loop on GR sensitivity.","evidence":"Synthesis of GR-chaperone biochemistry, cortisol-binding and induction assays","pmids":["19560279"],"confidence":"Medium","gaps":["Review-level synthesis; structural basis of GR-complex inhibition not resolved here","Quantitative contribution to in vivo HPA tone not defined"]},{"year":2011,"claim":"Knockout and Co-IP work tied FKBP5 directly to HPA-axis stress reactivity and to GSK3β regulation, broadening its role from receptor chaperone to stress-circuit and kinase scaffold.","evidence":"Fkbp5 KO mice with behavioral and corticosterone phenotyping; Co-IP, domain mapping, and KO validation of GSK3β(S9) phosphorylation","pmids":["21935478","25849320"],"confidence":"High","gaps":["Whether GSK3β and HPA effects share a common molecular pathway not resolved","PP2A/CDK5 roles within the heterocomplex not mechanistically dissected"]},{"year":2012,"claim":"A regulatory polymorphism was shown to enable trauma-dependent epigenetic disinhibition of FKBP5, providing a gene-by-environment mechanism for HPA dysregulation.","evidence":"3C chromatin conformation capture, bisulfite sequencing of intronic GREs, allele-specific expression in human cohorts and cells","pmids":["23201972"],"confidence":"High","gaps":["Causal link from demethylation to specific psychiatric outcomes not established","Tissue-specificity of demethylation incompletely mapped"]},{"year":2014,"claim":"FKBP51 was shown to chaperone the AKT phosphatase PHLPP and to drive an Akt-p38-PPARγ/GRα axis essential for adipogenesis, recasting it as a metabolic signaling scaffold acting through specific phospho-residues.","evidence":"KO MEFs with re-expression rescue, phospho-site mutants (PPARγ S112, GRα S220/S234), p38 inhibition, reporter and differentiation assays","pmids":["24933248","24933247"],"confidence":"High","gaps":["Stoichiometry of the FKBP51-PHLPP-AKT complex not defined","Tissue-level metabolic relevance addressed only in cell models here"]},{"year":2015,"claim":"FKBP51 was linked to Beclin-1-dependent autophagy as a required mediator of antidepressant action, connecting its scaffolding to a degradative pathway.","evidence":"FKBP51-BECN1 Co-IP, autophagic flux/LC3-II assays, KO mice with antidepressant behavioral testing","pmids":["25714272"],"confidence":"Medium","gaps":["Direct effect on Beclin-1 phosphorylation mechanism unresolved","Single-lab Co-IP without reciprocal structural validation"]},{"year":2017,"claim":"Cancer studies established FKBP51 as a scaffold enhancing PHLPP-AKT dephosphorylation, stabilized by deubiquitinases, and as a regulator of RhoA-ROCK motility and AKT-dependent glucose uptake, expanding its signaling reach.","evidence":"Co-IP and ubiquitination assays (USP49), AKT phospho-readouts in pancreatic cancer; IP-MS and RhoA/invasion assays (DLC1/DLC2); FKBP51-AS160 Co-IP, GLUT4 fractionation, KO-mouse and SAFit2 metabolic phenotyping","pmids":["28363942","28032931","29170369"],"confidence":"High","gaps":["Direct versus indirect nature of some interactions not fully resolved","How a single scaffold coordinates these divergent pathways in vivo unknown"]},{"year":2018,"claim":"FKBP51 was placed within an Hsp90/GR/IKK complex that drives NF-κB-dependent inflammation while restraining GR sensitivity, coupling immune and glucocorticoid signaling.","evidence":"Co-IP, siRNA silencing, NF-κB translocation and cytokine assays in bronchial epithelial cells; in vivo pulmonary inflammation model","pmids":["30169894"],"confidence":"Medium","gaps":["Whether FKBP51 directly templates IKK assembly not shown here","Single-lab evidence"]},{"year":2020,"claim":"Reciprocal Co-IP in human and mouse defined a GR-FKBP51 complex elevated in PTSD/fear that suppresses GR phosphorylation and nuclear entry and is therapeutically disruptable, while a second study extended FKBP5 to RIG-I-IKKα antiviral restriction and a third identified USP53 as an additional stabilizing deubiquitinase.","evidence":"Co-IP in human blood and mouse brain with peptide disruption and fear conditioning; FKBP5-IKKα Co-IP and IAV infection in KO cells; USP53 Co-IP/ubiquitination assay and xenograft","pmids":["31929189","32580383","32511815"],"confidence":"High","gaps":["Structural basis of the GR-FKBP51 interface for rational disruption not resolved","Generality of antiviral restriction across viruses untested"]},{"year":2021,"claim":"Multiple studies broadened FKBP5 control of steroid receptors and tissue physiology: MR sets baseline expression, FKBP51 inhibits PR to drive stress-induced preterm birth, regulates AR dimerization in prostate cancer, ERα stability, hippocampal synaptic plasticity, and decidual/trophoblast function via AKT.","evidence":"Biotin-oligo-IP and conditional MR KO; Fkbp5 KO with maternal-stress preterm-birth rescue and human decidua; AR dimerization/ChIP with FK1 inhibitor; ERα stability assays; KO-mouse electrophysiology; ESC shRNA/rescue","pmids":["34077736","33836562","34057812","35394865","30685540","29363568"],"confidence":"High","gaps":["How one scaffold selectively tunes opposing steroid receptors not unified","Cell-type determinants of these divergent outcomes unclear"]},{"year":2022,"claim":"Post-translational control was mechanistically established: SUMOylation via PIAS4 is required for FKBP51's GR inhibition and is blocked by tricyclic antidepressants, and FKBP51 was defined as a hypothalamic scaffold linking AMPK/WIPI and TSC2/WIPI to balance autophagy and mTOR and control body weight.","evidence":"In vitro SUMOylation, Co-IP of complex remodeling, PIAS4 siRNA and in vivo clomipramine; MBH-specific viral KO/overexpression with metabolomics and high-fat-diet phenotyping","pmids":["35256747","35263141"],"confidence":"High","gaps":["SUMO acceptor residues and their structural effect on GR binding not fully mapped here","Interplay between PTMs and scaffolding selectivity unresolved"]},{"year":2023,"claim":"A series of studies localized FKBP5 scaffolding to specific tissues and modifications: CBD binding at Y113 blocks IKK assembly, FKBP5-Hsp90 competition limits HIF-1α/NCX1 to prevent arrhythmia, SIRT1 deacetylation dissociates FKBP5 from GR, and FKBP5 regulates β-cell FOXO1 and oligodendrocyte mitophagy.","evidence":"Direct binding/CETSA and Y113A mutagenesis with IKK Co-IP; cardiomyocyte conditional KO with electrophysiology and Hsp90-HIF-1α Co-IP; SIRT1-FKBP5-GR Co-IP with BNST manipulation; β-cell siRNA/SAFit2 epistasis; cuprizone KO with mitophagy markers","pmids":["37196785","37154033","37386058","37452039","37952053"],"confidence":"High","gaps":["Whether these tissue mechanisms share a common scaffolding module untested","Direct vs indirect engagement of Hsp90 partners in some contexts unresolved"]},{"year":2024,"claim":"SKA2 was shown to remodel the GR chaperone complex by promoting GR-FKBP52 interaction and FKBP51 dissociation, identifying an upstream determinant of FKBP51's GR-restraining state in HPA-axis feedback.","evidence":"Cell-based Co-IP and conditional CRH-neuron SKA2 manipulation with corticosterone readouts; postmortem human expression","pmids":["39705315"],"confidence":"Medium","gaps":["Direct vs indirect SKA2 action on the complex not resolved","Single-lab in vivo evidence"]},{"year":null,"claim":"It remains unknown how a single immunophilin scaffold achieves selective, tissue-specific control across so many client complexes, and what structural/PTM code dictates whether FKBP51 inhibits or promotes a given receptor or kinase pathway.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified structural model of client selectivity","PTM-to-function mapping incomplete","Causal links from human variants/methylation to disease phenotypes not fully established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[3,10,14,27,30]},{"term_id":"GO:0044183","term_label":"protein folding chaperone","supporting_discovery_ids":[3,10,31]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3,7,16,22]},{"term_id":"GO:0016853","term_label":"isomerase activity","supporting_discovery_ids":[28]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[3,10,14]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[3,7,16,22]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,7,10,16]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[14,18,30]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[9,20,27]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[8,12,27,32]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[3,5,6,16]}],"complexes":["GR-Hsp90 heterocomplex","IKK complex","FKBP51-PHLPP-AKT complex","GSK3β heterocomplex"],"partners":["HSP90","NR3C1","PHLPP","AKT1","BECN1","PIAS4","SIRT1","PPP3 (CALCINEURIN)"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q13451","full_name":"Peptidyl-prolyl cis-trans isomerase FKBP5","aliases":["51 kDa FK506-binding protein","51 kDa FKBP","FKBP-51","54 kDa progesterone receptor-associated immunophilin","Androgen-regulated protein 6","FF1 antigen","FK506-binding protein 5","FKBP-5","FKBP54","p54","HSP90-binding immunophilin","Rotamase"],"length_aa":457,"mass_kda":51.2,"function":"Immunophilin protein with PPIase and co-chaperone activities (PubMed:11350175). Component of unligated steroid receptors heterocomplexes through interaction with heat-shock protein 90 (HSP90). Plays a role in the intracellular trafficking of heterooligomeric forms of steroid hormone receptors maintaining the complex into the cytoplasm when unliganded (PubMed:12538866). Acts as a regulator of Akt/AKT1 activity by promoting the interaction between Akt/AKT1 and PHLPP1, thereby enhancing dephosphorylation and subsequent activation of Akt/AKT1 (PubMed:28147277, PubMed:28363942). Interacts with IKBKE and IKBKB which facilitates IKK complex assembly leading to increased IKBKE and IKBKB kinase activity, NF-kappa-B activation, and IFN production (PubMed:26101251, PubMed:31434731)","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q13451/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/FKBP5","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000096060","cell_line_id":"CID000940","localizations":[{"compartment":"nucleoplasm","grade":3}],"interactors":[{"gene":"CDC37","stoichiometry":10.0},{"gene":"CHD7","stoichiometry":10.0},{"gene":"AHSA1","stoichiometry":4.0},{"gene":"SUGT1","stoichiometry":4.0},{"gene":"CDK9","stoichiometry":4.0},{"gene":"AGO2","stoichiometry":0.2},{"gene":"CAPZB","stoichiometry":0.2},{"gene":"DNAJB6","stoichiometry":0.2},{"gene":"PRPF8","stoichiometry":0.2},{"gene":"TTC37","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000940","total_profiled":1310},"omim":[{"mim_id":"621120","title":"DELTA-LIKE NONCANONICAL NOTCH LIGAND 2; DLK2","url":"https://www.omim.org/entry/621120"},{"mim_id":"608516","title":"MAJOR DEPRESSIVE DISORDER; MDD","url":"https://www.omim.org/entry/608516"},{"mim_id":"606599","title":"THIOREDOXIN-INTERACTING PROTEIN; TXNIP","url":"https://www.omim.org/entry/606599"},{"mim_id":"605644","title":"KALLIKREIN-RELATED PEPTIDASE 8; KLK8","url":"https://www.omim.org/entry/605644"},{"mim_id":"602623","title":"FK506-BINDING PROTEIN 5; FKBP5","url":"https://www.omim.org/entry/602623"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Nucleoli fibrillar center","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"skeletal muscle","ntpm":833.2},{"tissue":"tongue","ntpm":864.2}],"url":"https://www.proteinatlas.org/search/FKBP5"},"hgnc":{"alias_symbol":["FKBP51","FKBP54","PPIase","P54","Ptg-10"],"prev_symbol":[]},"alphafold":{"accession":"Q13451","domains":[{"cath_id":"3.10.50.40","chopping":"17-139","consensus_level":"high","plddt":96.521,"start":17,"end":139},{"cath_id":"3.10.50.40","chopping":"149-252","consensus_level":"high","plddt":97.6868,"start":149,"end":252},{"cath_id":"1.25.40.10","chopping":"262-398","consensus_level":"medium","plddt":97.8791,"start":262,"end":398}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13451","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q13451-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q13451-F1-predicted_aligned_error_v6.png","plddt_mean":92.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=FKBP5","jax_strain_url":"https://www.jax.org/strain/search?query=FKBP5"},"sequence":{"accession":"Q13451","fasta_url":"https://rest.uniprot.org/uniprotkb/Q13451.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q13451/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13451"}},"corpus_meta":[{"pmid":"23201972","id":"PMC_23201972","title":"Allele-specific FKBP5 DNA demethylation mediates gene-childhood trauma interactions.","date":"2012","source":"Nature neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/23201972","citation_count":1030,"is_preprint":false},{"pmid":"19560279","id":"PMC_19560279","title":"The role of FKBP5, a co-chaperone of the glucocorticoid receptor in the pathogenesis and therapy of affective and anxiety disorders.","date":"2009","source":"Psychoneuroendocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/19560279","citation_count":752,"is_preprint":false},{"pmid":"26250598","id":"PMC_26250598","title":"Gene-Stress-Epigenetic Regulation of FKBP5: Clinical and Translational Implications.","date":"2015","source":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/26250598","citation_count":464,"is_preprint":false},{"pmid":"26410355","id":"PMC_26410355","title":"Holocaust Exposure Induced Intergenerational Effects on FKBP5 Methylation.","date":"2015","source":"Biological psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/26410355","citation_count":357,"is_preprint":false},{"pmid":"24219237","id":"PMC_24219237","title":"Gene-environment interactions at the FKBP5 locus: sensitive periods, mechanisms and pleiotropism.","date":"2013","source":"Genes, brain, and behavior","url":"https://pubmed.ncbi.nlm.nih.gov/24219237","citation_count":221,"is_preprint":false},{"pmid":"21889356","id":"PMC_21889356","title":"FKBP51 and FKBP52 in signaling and disease.","date":"2011","source":"Trends in endocrinology and metabolism: TEM","url":"https://pubmed.ncbi.nlm.nih.gov/21889356","citation_count":217,"is_preprint":false},{"pmid":"20668026","id":"PMC_20668026","title":"Chronic corticosterone exposure increases expression and decreases deoxyribonucleic acid methylation of Fkbp5 in mice.","date":"2010","source":"Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/20668026","citation_count":214,"is_preprint":false},{"pmid":"29573791","id":"PMC_29573791","title":"Understanding the Molecular Mechanisms Underpinning Gene by Environment Interactions in Psychiatric Disorders: The FKBP5 Model.","date":"2018","source":"Biological psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/29573791","citation_count":192,"is_preprint":false},{"pmid":"21347384","id":"PMC_21347384","title":"Expression and regulation of the Fkbp5 gene in the adult mouse brain.","date":"2011","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/21347384","citation_count":181,"is_preprint":false},{"pmid":"21531172","id":"PMC_21531172","title":"Steroid up-regulation of FKBP51 and its role in hormone signaling.","date":"2011","source":"Current opinion in pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/21531172","citation_count":134,"is_preprint":false},{"pmid":"29206196","id":"PMC_29206196","title":"The FKBP51 Glucocorticoid Receptor Co-Chaperone: Regulation, Function, and Implications in Health and Disease.","date":"2017","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/29206196","citation_count":131,"is_preprint":false},{"pmid":"29203717","id":"PMC_29203717","title":"Hsp90 and FKBP51: complex regulators of psychiatric diseases.","date":"2018","source":"Philosophical transactions of the Royal Society of London. Series B, Biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/29203717","citation_count":116,"is_preprint":false},{"pmid":"21935478","id":"PMC_21935478","title":"A new anti-depressive strategy for the elderly: ablation of FKBP5/FKBP51.","date":"2011","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/21935478","citation_count":108,"is_preprint":false},{"pmid":"21119664","id":"PMC_21119664","title":"The role of FKBP5 in cancer aetiology and chemoresistance.","date":"2010","source":"British journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/21119664","citation_count":107,"is_preprint":false},{"pmid":"9125197","id":"PMC_9125197","title":"Tissue distribution and abundance of human FKBP51, and FK506-binding protein that can mediate calcineurin inhibition.","date":"1997","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/9125197","citation_count":107,"is_preprint":false},{"pmid":"23407841","id":"PMC_23407841","title":"FKBP5 and attention bias for threat: associations with hippocampal function and shape.","date":"2013","source":"JAMA psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/23407841","citation_count":105,"is_preprint":false},{"pmid":"29170369","id":"PMC_29170369","title":"Stress-responsive FKBP51 regulates AKT2-AS160 signaling and metabolic function.","date":"2017","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/29170369","citation_count":97,"is_preprint":false},{"pmid":"30669684","id":"PMC_30669684","title":"The Many Faces of FKBP51.","date":"2019","source":"Biomolecules","url":"https://pubmed.ncbi.nlm.nih.gov/30669684","citation_count":95,"is_preprint":false},{"pmid":"26535949","id":"PMC_26535949","title":"Childhood maltreatment and methylation of FK506 binding protein 5 gene (FKBP5).","date":"2015","source":"Development and psychopathology","url":"https://pubmed.ncbi.nlm.nih.gov/26535949","citation_count":93,"is_preprint":false},{"pmid":"28363942","id":"PMC_28363942","title":"USP49 negatively regulates tumorigenesis and chemoresistance through FKBP51-AKT signaling.","date":"2017","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/28363942","citation_count":91,"is_preprint":false},{"pmid":"34077736","id":"PMC_34077736","title":"Mineralocorticoid receptors dampen glucocorticoid receptor sensitivity to stress via regulation of FKBP5.","date":"2021","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/34077736","citation_count":86,"is_preprint":false},{"pmid":"25714272","id":"PMC_25714272","title":"FKBP5/FKBP51 enhances autophagy to synergize with antidepressant action.","date":"2015","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/25714272","citation_count":82,"is_preprint":false},{"pmid":"30717249","id":"PMC_30717249","title":"Biological Actions of the Hsp90-binding Immunophilins FKBP51 and FKBP52.","date":"2019","source":"Biomolecules","url":"https://pubmed.ncbi.nlm.nih.gov/30717249","citation_count":79,"is_preprint":false},{"pmid":"21565552","id":"PMC_21565552","title":"FKBP51-a selective modulator of glucocorticoid and androgen sensitivity.","date":"2011","source":"Current opinion in pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/21565552","citation_count":72,"is_preprint":false},{"pmid":"7693698","id":"PMC_7693698","title":"FKBP54, a novel FK506-binding protein in avian progesterone receptor complexes and HeLa extracts.","date":"1993","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/7693698","citation_count":64,"is_preprint":false},{"pmid":"30700816","id":"PMC_30700816","title":"Methylation of the FKBP5 gene in association with FKBP5 genotypes, childhood maltreatment and depression.","date":"2019","source":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/30700816","citation_count":63,"is_preprint":false},{"pmid":"31668388","id":"PMC_31668388","title":"Focus on FKBP51: A molecular link between stress and metabolic disorders.","date":"2019","source":"Molecular metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/31668388","citation_count":59,"is_preprint":false},{"pmid":"34481731","id":"PMC_34481731","title":"FKBP51 and the molecular chaperoning of metabolism.","date":"2021","source":"Trends in endocrinology and metabolism: TEM","url":"https://pubmed.ncbi.nlm.nih.gov/34481731","citation_count":57,"is_preprint":false},{"pmid":"37196785","id":"PMC_37196785","title":"Cannabidiol alleviates neuroinflammation and attenuates neuropathic pain via targeting FKBP5.","date":"2023","source":"Brain, behavior, and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/37196785","citation_count":56,"is_preprint":false},{"pmid":"24253961","id":"PMC_24253961","title":"FKBP5 genotype and structural integrity of the posterior cingulum.","date":"2013","source":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/24253961","citation_count":55,"is_preprint":false},{"pmid":"21514887","id":"PMC_21514887","title":"Organization and function of the FKBP52 and FKBP51 genes.","date":"2011","source":"Current opinion in pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/21514887","citation_count":54,"is_preprint":false},{"pmid":"31929189","id":"PMC_31929189","title":"The glucocorticoid receptor-FKBP51 complex contributes to fear conditioning and posttraumatic stress disorder.","date":"2020","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/31929189","citation_count":54,"is_preprint":false},{"pmid":"34024231","id":"PMC_34024231","title":"Modulating FKBP5/FKBP51 and autophagy lowers HTT (huntingtin) levels.","date":"2021","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/34024231","citation_count":53,"is_preprint":false},{"pmid":"25849320","id":"PMC_25849320","title":"FKBP51 inhibits GSK3β and augments the effects of distinct psychotropic medications.","date":"2015","source":"Molecular psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/25849320","citation_count":53,"is_preprint":false},{"pmid":"30273884","id":"PMC_30273884","title":"GxE effects of FKBP5 and traumatic life events on PTSD: A meta-analysis.","date":"2018","source":"Journal of affective disorders","url":"https://pubmed.ncbi.nlm.nih.gov/30273884","citation_count":52,"is_preprint":false},{"pmid":"32312110","id":"PMC_32312110","title":"Intergenerational Effects of Maternal Holocaust Exposure on FKBP5 Methylation.","date":"2020","source":"The American journal of psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/32312110","citation_count":52,"is_preprint":false},{"pmid":"27374865","id":"PMC_27374865","title":"FK506 binding protein 51 integrates pathways of adaptation: FKBP51 shapes the reactivity to environmental change.","date":"2016","source":"BioEssays : news and reviews in molecular, cellular and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/27374865","citation_count":49,"is_preprint":false},{"pmid":"30334356","id":"PMC_30334356","title":"DNA methylation of FKBP5 and response to exposure-based psychological therapy.","date":"2018","source":"American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/30334356","citation_count":48,"is_preprint":false},{"pmid":"30169894","id":"PMC_30169894","title":"FKBP51 modulates steroid sensitivity and NFκB signalling: A novel anti-inflammatory drug target.","date":"2018","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/30169894","citation_count":46,"is_preprint":false},{"pmid":"36729133","id":"PMC_36729133","title":"Associations of psychiatric disease and ageing with FKBP5 expression converge on superficial layer neurons of the neocortex.","date":"2023","source":"Acta neuropathologica","url":"https://pubmed.ncbi.nlm.nih.gov/36729133","citation_count":45,"is_preprint":false},{"pmid":"24933247","id":"PMC_24933247","title":"FKBP51 controls cellular adipogenesis through p38 kinase-mediated phosphorylation of GRα and PPARγ.","date":"2014","source":"Molecular endocrinology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/24933247","citation_count":45,"is_preprint":false},{"pmid":"30605803","id":"PMC_30605803","title":"Allele-specific DNA methylation level of FKBP5 is associated with post-traumatic stress disorder.","date":"2018","source":"Psychoneuroendocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/30605803","citation_count":45,"is_preprint":false},{"pmid":"21498116","id":"PMC_21498116","title":"FKBP51 regulation of AKT/protein kinase B phosphorylation.","date":"2011","source":"Current opinion in pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/21498116","citation_count":44,"is_preprint":false},{"pmid":"24933248","id":"PMC_24933248","title":"FKBP51 reciprocally regulates GRα and PPARγ activation via the Akt-p38 pathway.","date":"2014","source":"Molecular endocrinology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/24933248","citation_count":44,"is_preprint":false},{"pmid":"33666419","id":"PMC_33666419","title":"Structure-Based Design of High-Affinity Macrocyclic FKBP51 Inhibitors.","date":"2021","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/33666419","citation_count":40,"is_preprint":false},{"pmid":"25986564","id":"PMC_25986564","title":"The FKBP51-Glucocorticoid Receptor Balance in Stress-Related Mental Disorders.","date":"2015","source":"Current molecular pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/25986564","citation_count":39,"is_preprint":false},{"pmid":"27459525","id":"PMC_27459525","title":"FKBP5 mRNA Expression Is a Biomarker for GR Antagonism.","date":"2016","source":"The Journal of clinical endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/27459525","citation_count":39,"is_preprint":false},{"pmid":"34589890","id":"PMC_34589890","title":"FKBP5 and early life stress affect the hippocampus by an age-dependent mechanism.","date":"2020","source":"Brain, behavior, & immunity - health","url":"https://pubmed.ncbi.nlm.nih.gov/34589890","citation_count":37,"is_preprint":false},{"pmid":"37398599","id":"PMC_37398599","title":"Role of FKBP5 and its genetic mutations in stress-induced psychiatric disorders: an opportunity for drug discovery.","date":"2023","source":"Frontiers in psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/37398599","citation_count":36,"is_preprint":false},{"pmid":"21565553","id":"PMC_21565553","title":"FKBP51 and the NF-κB regulatory pathway in cancer.","date":"2011","source":"Current opinion in pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/21565553","citation_count":36,"is_preprint":false},{"pmid":"11813252","id":"PMC_11813252","title":"Calcium- and FK506-independent interaction between the immunophilin FKBP51 and calcineurin.","date":"2002","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11813252","citation_count":34,"is_preprint":false},{"pmid":"27664120","id":"PMC_27664120","title":"Reduced DNA methylation of FKBP5 in Cushing's syndrome.","date":"2016","source":"Endocrine","url":"https://pubmed.ncbi.nlm.nih.gov/27664120","citation_count":33,"is_preprint":false},{"pmid":"37827456","id":"PMC_37827456","title":"FKBP5 regulates trophoblast-macrophage crosstalk in recurrent spontaneous abortion through PI3K/AKT and NF-κB signaling pathways.","date":"2023","source":"Free radical biology & medicine","url":"https://pubmed.ncbi.nlm.nih.gov/37827456","citation_count":32,"is_preprint":false},{"pmid":"36104438","id":"PMC_36104438","title":"Inhibition of FKBP51 induces stress resilience and alters hippocampal neurogenesis.","date":"2022","source":"Molecular psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/36104438","citation_count":32,"is_preprint":false},{"pmid":"30685540","id":"PMC_30685540","title":"Loss of FKBP5 Affects Neuron Synaptic Plasticity: An Electrophysiology Insight.","date":"2019","source":"Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/30685540","citation_count":32,"is_preprint":false},{"pmid":"32511815","id":"PMC_32511815","title":"USP53 promotes apoptosis and inhibits glycolysis in lung adenocarcinoma through FKBP51-AKT1 signaling.","date":"2020","source":"Molecular carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/32511815","citation_count":31,"is_preprint":false},{"pmid":"34057812","id":"PMC_34057812","title":"FKBP51 and FKBP52 regulate androgen receptor dimerization and proliferation in prostate cancer cells.","date":"2021","source":"Molecular oncology","url":"https://pubmed.ncbi.nlm.nih.gov/34057812","citation_count":29,"is_preprint":false},{"pmid":"32580383","id":"PMC_32580383","title":"FKBP5 Regulates RIG-I-Mediated NF-κB Activation and Influenza A Virus Infection.","date":"2020","source":"Viruses","url":"https://pubmed.ncbi.nlm.nih.gov/32580383","citation_count":29,"is_preprint":false},{"pmid":"33836562","id":"PMC_33836562","title":"Decidual cell FKBP51-progesterone receptor binding mediates maternal stress-induced preterm birth.","date":"2021","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/33836562","citation_count":27,"is_preprint":false},{"pmid":"29674169","id":"PMC_29674169","title":"Intergenerational gene × environment interaction of FKBP5 and childhood maltreatment on hair steroids.","date":"2018","source":"Psychoneuroendocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/29674169","citation_count":27,"is_preprint":false},{"pmid":"37952053","id":"PMC_37952053","title":"FKBP5 activates mitophagy by ablating PPAR-γ to shape a benign remyelination environment.","date":"2023","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/37952053","citation_count":25,"is_preprint":false},{"pmid":"28524179","id":"PMC_28524179","title":"A FKBP5 mutation is associated with Paget's disease of bone and enhances osteoclastogenesis.","date":"2017","source":"Experimental & molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/28524179","citation_count":25,"is_preprint":false},{"pmid":"35394865","id":"PMC_35394865","title":"FKBP52 and FKBP51 differentially regulate the stability of estrogen receptor in breast cancer.","date":"2022","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/35394865","citation_count":24,"is_preprint":false},{"pmid":"37252963","id":"PMC_37252963","title":"Sex-specific and opposed effects of FKBP51 in glutamatergic and GABAergic neurons: Implications for stress susceptibility and resilience.","date":"2023","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/37252963","citation_count":24,"is_preprint":false},{"pmid":"30953930","id":"PMC_30953930","title":"Interactions between FKBP5 variation and environmental stressors in adolescent Major Depression.","date":"2019","source":"Psychoneuroendocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/30953930","citation_count":24,"is_preprint":false},{"pmid":"27648526","id":"PMC_27648526","title":"The influence of FKBP5 genotype on expression of FKBP5 and other glucocorticoid-regulated genes, dependent on trauma exposure.","date":"2016","source":"Genes, brain, and behavior","url":"https://pubmed.ncbi.nlm.nih.gov/27648526","citation_count":24,"is_preprint":false},{"pmid":"34433110","id":"PMC_34433110","title":"Regulatory functions of FKBP5 intronic regions associated with psychiatric disorders.","date":"2021","source":"Journal of psychiatric research","url":"https://pubmed.ncbi.nlm.nih.gov/34433110","citation_count":23,"is_preprint":false},{"pmid":"33843131","id":"PMC_33843131","title":"Macrocyclic FKBP51 Ligands Define a Transient Binding Mode with Enhanced Selectivity.","date":"2021","source":"Angewandte Chemie (International ed. in English)","url":"https://pubmed.ncbi.nlm.nih.gov/33843131","citation_count":23,"is_preprint":false},{"pmid":"37452039","id":"PMC_37452039","title":"The inhibition of FKBP5 protects β-cell survival under inflammation stress via AKT/FOXO1 signaling.","date":"2023","source":"Cell death discovery","url":"https://pubmed.ncbi.nlm.nih.gov/37452039","citation_count":22,"is_preprint":false},{"pmid":"35263141","id":"PMC_35263141","title":"Mediobasal hypothalamic FKBP51 acts as a molecular switch linking autophagy to whole-body metabolism.","date":"2022","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/35263141","citation_count":22,"is_preprint":false},{"pmid":"37386058","id":"PMC_37386058","title":"SIRT1 in the BNST modulates chronic stress-induced anxiety of male mice via FKBP5 and corticotropin-releasing factor signaling.","date":"2023","source":"Molecular psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/37386058","citation_count":21,"is_preprint":false},{"pmid":"36781843","id":"PMC_36781843","title":"Methylation and expression of glucocorticoid receptor exon-1 variants and FKBP5 in teenage suicide-completers.","date":"2023","source":"Translational psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/36781843","citation_count":21,"is_preprint":false},{"pmid":"32323357","id":"PMC_32323357","title":"Peptidylprolylisomerases, Protein Folders, or Scaffolders? The Example of FKBP51 and FKBP52.","date":"2020","source":"BioEssays : news and reviews in molecular, cellular and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/32323357","citation_count":21,"is_preprint":false},{"pmid":"33255215","id":"PMC_33255215","title":"Adverse Childhood Experiences and Methylation of the FKBP5 Gene in Patients with Psychotic Disorders.","date":"2020","source":"Journal of clinical medicine","url":"https://pubmed.ncbi.nlm.nih.gov/33255215","citation_count":21,"is_preprint":false},{"pmid":"37154033","id":"PMC_37154033","title":"Downregulation of FKBP5 Promotes Atrial Arrhythmogenesis.","date":"2023","source":"Circulation research","url":"https://pubmed.ncbi.nlm.nih.gov/37154033","citation_count":20,"is_preprint":false},{"pmid":"31754722","id":"PMC_31754722","title":"Regulation of FKBP51 and FKBP52 functions by post-translational modifications.","date":"2019","source":"Biochemical Society transactions","url":"https://pubmed.ncbi.nlm.nih.gov/31754722","citation_count":20,"is_preprint":false},{"pmid":"35438043","id":"PMC_35438043","title":"FKBP5/FKBP51 on weight watch: central FKBP5 links regulatory WIPI protein networks to autophagy and metabolic control.","date":"2022","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/35438043","citation_count":20,"is_preprint":false},{"pmid":"27638035","id":"PMC_27638035","title":"Association between FKBP5 and CRHR1 genes with suicidal behavior: A systematic review.","date":"2016","source":"Behavioural brain research","url":"https://pubmed.ncbi.nlm.nih.gov/27638035","citation_count":20,"is_preprint":false},{"pmid":"28032931","id":"PMC_28032931","title":"FKBP51 regulates cell motility and invasion via RhoA signaling.","date":"2017","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/28032931","citation_count":19,"is_preprint":false},{"pmid":"34713710","id":"PMC_34713710","title":"Blood-Based Epigenetic Markers of FKBP5 Gene Methylation in Patients With Dilated Cardiomyopathy.","date":"2021","source":"Journal of the American Heart Association","url":"https://pubmed.ncbi.nlm.nih.gov/34713710","citation_count":19,"is_preprint":false},{"pmid":"28254433","id":"PMC_28254433","title":"Loss of FKBP5 impedes adipocyte differentiation under both normoxia and hypoxic stress.","date":"2017","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/28254433","citation_count":19,"is_preprint":false},{"pmid":"33742763","id":"PMC_33742763","title":"Association of FKBP5 gene variants with depression susceptibility: A comprehensive meta-analysis.","date":"2021","source":"Asia-Pacific psychiatry : official journal of the Pacific Rim College of Psychiatrists","url":"https://pubmed.ncbi.nlm.nih.gov/33742763","citation_count":18,"is_preprint":false},{"pmid":"32958048","id":"PMC_32958048","title":"DNA methylation of FKBP5 in South African women: associations with obesity and insulin resistance.","date":"2020","source":"Clinical epigenetics","url":"https://pubmed.ncbi.nlm.nih.gov/32958048","citation_count":18,"is_preprint":false},{"pmid":"29363568","id":"PMC_29363568","title":"FKBP51 regulates decidualization through Ser473 dephosphorylation of AKT.","date":"2018","source":"Reproduction (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/29363568","citation_count":18,"is_preprint":false},{"pmid":"33319620","id":"PMC_33319620","title":"Characterization of glucocorticoid-induced loss of DNA methylation of the stress-response gene Fkbp5 in neuronal cells.","date":"2021","source":"Epigenetics","url":"https://pubmed.ncbi.nlm.nih.gov/33319620","citation_count":18,"is_preprint":false},{"pmid":"24694367","id":"PMC_24694367","title":"Molecular chaperone activity and biological regulatory actions of the TPR-domain immunophilins FKBP51 and FKBP52.","date":"2014","source":"Current protein & peptide science","url":"https://pubmed.ncbi.nlm.nih.gov/24694367","citation_count":17,"is_preprint":false},{"pmid":"26456144","id":"PMC_26456144","title":"FKBP5 risk alleles and the development of intrusive memories.","date":"2015","source":"Neurobiology of learning and memory","url":"https://pubmed.ncbi.nlm.nih.gov/26456144","citation_count":17,"is_preprint":false},{"pmid":"32488091","id":"PMC_32488091","title":"No association between FKBP5 gene methylation and acute and long-term cortisol output.","date":"2020","source":"Translational psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/32488091","citation_count":16,"is_preprint":false},{"pmid":"28002634","id":"PMC_28002634","title":"FKBP5 polymorphisms influence pre-learning stress-induced alterations of learning and memory.","date":"2017","source":"The European journal of neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/28002634","citation_count":16,"is_preprint":false},{"pmid":"39705315","id":"PMC_39705315","title":"SKA2 enhances stress-related glucocorticoid receptor signaling through FKBP4-FKBP5 interactions in neurons.","date":"2024","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/39705315","citation_count":15,"is_preprint":false},{"pmid":"27915167","id":"PMC_27915167","title":"Examining FKBP5 mRNA expression in human iPSC-derived neural cells.","date":"2016","source":"Psychiatry research","url":"https://pubmed.ncbi.nlm.nih.gov/27915167","citation_count":15,"is_preprint":false},{"pmid":"30711865","id":"PMC_30711865","title":"FKBP5 gene variants and borderline personality disorder.","date":"2019","source":"Journal of affective disorders","url":"https://pubmed.ncbi.nlm.nih.gov/30711865","citation_count":14,"is_preprint":false},{"pmid":"34830120","id":"PMC_34830120","title":"Crabp1 Modulates HPA Axis Homeostasis and Anxiety-like Behaviors by Altering FKBP5 Expression.","date":"2021","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/34830120","citation_count":14,"is_preprint":false},{"pmid":"34072036","id":"PMC_34072036","title":"Differential Effects of Fkbp4 and Fkbp5 on Regulation of the Proopiomelanocortin Gene in Murine AtT-20 Corticotroph Cells.","date":"2021","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/34072036","citation_count":14,"is_preprint":false},{"pmid":"39905728","id":"PMC_39905728","title":"FKBP51 inhibition ameliorates neurodegeneration and motor dysfunction in the neuromelanin-SNCA mouse model of Parkinson's disease.","date":"2025","source":"Molecular therapy : the journal of the American Society of Gene Therapy","url":"https://pubmed.ncbi.nlm.nih.gov/39905728","citation_count":13,"is_preprint":false},{"pmid":"35256747","id":"PMC_35256747","title":"Tricyclic antidepressants target FKBP51 SUMOylation to restore glucocorticoid receptor activity.","date":"2022","source":"Molecular psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/35256747","citation_count":13,"is_preprint":false},{"pmid":"36933666","id":"PMC_36933666","title":"DNA methylation in regulatory elements of the FKBP5 and NR3C1 gene in mother-child binomials with depression.","date":"2023","source":"Journal of affective disorders","url":"https://pubmed.ncbi.nlm.nih.gov/36933666","citation_count":13,"is_preprint":false},{"pmid":"34896595","id":"PMC_34896595","title":"Cadmium regulates FKBP5 through miR-9-5p and induces carp lymphocyte apoptosis.","date":"2021","source":"Fish & shellfish immunology","url":"https://pubmed.ncbi.nlm.nih.gov/34896595","citation_count":13,"is_preprint":false},{"pmid":"37777763","id":"PMC_37777763","title":"A DNA methylation signature in the stress driver gene Fkbp5 indicates a neuropathic component in chronic pain.","date":"2023","source":"Clinical epigenetics","url":"https://pubmed.ncbi.nlm.nih.gov/37777763","citation_count":13,"is_preprint":false},{"pmid":"31800244","id":"PMC_31800244","title":"A Novel Decalin-Based Bicyclic Scaffold for FKBP51-Selective Ligands.","date":"2019","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/31800244","citation_count":13,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":50730,"output_tokens":10562,"usd":0.15531,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":20871,"output_tokens":6014,"usd":0.127353,"stage2_stop_reason":"end_turn"},"total_usd":0.282663,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1993,\n      \"finding\": \"FKBP5 (FKBP54) was identified as a novel FK506-binding immunophilin that co-purifies with avian progesterone receptor complexes. It binds FK506 affinity resin and exists predominantly in oligomeric complexes at low ionic strength, distinct from FKBP52 (p50).\",\n      \"method\": \"FK506 affinity chromatography, glycerol density gradient sedimentation, immunoprecipitation with anti-p54 antibody\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical purification and affinity chromatography from native complexes, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"7693698\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Human FKBP51 (encoded by FKBP5) mediates FK506-dependent inhibition of calcineurin phosphatase activity in vitro, is induced by glucocorticoids in human T cells, and is abundantly expressed across numerous human tissues.\",\n      \"method\": \"In vitro calcineurin phosphatase inhibition assay, Western blot of 17 human tissues, glucocorticoid induction in C7TK.4 cells\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro enzymatic assay with protein purification, multiple tissues and cell lines, single lab\",\n      \"pmids\": [\"9125197\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"FKBP51 interacts directly with calcineurin in a manner that is independent of FK506, calcium, and calmodulin. The C-terminal domain (TPR domain) of FKBP51, not the FK1 (PPIase) domain, is required for calcineurin binding. Unlike FKBP12, FKBP51 overexpression did not significantly affect NFAT-driven transcription.\",\n      \"method\": \"GST pulldown with purified calcineurin and T cell lysates, calmodulin-Sepharose co-precipitation, FKBP51 deletion mutants, NFAT reporter assay in Jurkat T cells\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — reconstituted pulldown with purified proteins, domain mapping by deletion mutagenesis, functional reporter assay; multiple orthogonal methods in single study\",\n      \"pmids\": [\"11813252\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"FKBP51 acts as an Hsp90 co-chaperone in the glucocorticoid receptor (GR) complex; when bound, cortisol affinity for GR is reduced and nuclear translocation is less efficient. FKBP5 mRNA and protein are induced by GR activation via intronic hormone response elements, forming an ultra-short negative feedback loop for GR sensitivity.\",\n      \"method\": \"Pharmacological and molecular characterization of GR-chaperone complexes; GR sensitivity and cortisol-binding assays; FKBP5 induction experiments with glucocorticoids\",\n      \"journal\": \"Psychoneuroendocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Strong — well-replicated mechanistic model from multiple labs; review synthesizing experimental data; mechanism established in original biochemical studies cited within\",\n      \"pmids\": [\"19560279\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"FKBP51 associates with GSK3β mainly through its FK1 domain and increases phosphorylation of GSK3β at serine 9 (inhibitory phosphorylation). FKBP51 also associates with PP2A and CDK5 within the GSK3β heterocomplex, and acts through GSK3β on downstream targets Tau, β-catenin, and TCF/LEF. Deletion of FKBP51 blunted lithium- or paroxetine-induced pGSK3β(S9) increase in cells and mice.\",\n      \"method\": \"Co-immunoprecipitation, reporter gene assays, protein association analyses, FKBP51 knockout mouse experiments, domain mapping (FK1 domain)\",\n      \"journal\": \"Molecular psychiatry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, domain mapping, KO mouse validation, multiple downstream readouts in single study\",\n      \"pmids\": [\"25849320\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"FKBP51 knockout mice show antidepressant-like behavior with reduced post-stress corticosterone levels and modulated age-dependent anxiety, demonstrating that FKBP51 regulates HPA axis stress reactivity in vivo.\",\n      \"method\": \"FKBP5 knockout mouse model, behavioral assays (forced swim, elevated plus maze), corticosterone measurements\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with defined behavioral and neuroendocrine phenotype, single lab\",\n      \"pmids\": [\"21935478\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"A functional FKBP5 polymorphism (rs1360780) alters chromatin interaction between the transcription start site and long-range enhancers, enabling allele-specific, childhood trauma-dependent DNA demethylation at glucocorticoid response elements in FKBP5 introns. This demethylation increases stress-dependent FKBP5 transcription and dysregulates the HPA axis.\",\n      \"method\": \"Chromatin conformation capture (3C), bisulfite sequencing of GRE CpG sites, allele-specific expression analysis, cortisol/ACTH measurements in human cohorts and cell lines\",\n      \"journal\": \"Nature neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — chromatin conformation capture, allele-specific methylation quantification, functional expression assays; replicated in human cohorts and cellular models\",\n      \"pmids\": [\"23201972\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"FKBP51 reciprocally regulates GRα and PPARγ via the Akt-p38 kinase pathway. FKBP51 acts as an essential chaperone to the Akt-specific phosphatase PHLPP, thereby suppressing Akt and downstream p38 kinase activity. Loss of FKBP51 increases phosphorylation of PPARγ at S112 (inhibitory) and GRα at S220/S234 (activating), and shifts both receptors to the nucleus.\",\n      \"method\": \"FKBP51 knockout (51KO) MEFs, overexpression in COS-7 cells, reporter gene assays, western blotting for phosphorylation, p38 kinase inhibitor (PD169316), subcellular fractionation\",\n      \"journal\": \"Molecular endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — KO MEFs with rescue, pharmacological inhibition, phospho-site mapping, multiple orthogonal methods in single study\",\n      \"pmids\": [\"24933248\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"FKBP51 is a required regulator of adipogenesis: FKBP51 KO MEFs show near-complete resistance to differentiation with reduced lipid accumulation, reduced PPARγ activity, elevated GRα transrepression, and reduced fatty acid synthase activity. Rescue by re-expression of FKBP51 confirmed specificity. The S112A PPARγ and triple S212A/S220A/S234A GRα mutants partially restored lipid accumulation in KO cells, identifying these phospho-residues as targets of the FKBP51/p38 axis.\",\n      \"method\": \"3T3-L1 FKBP51 knockdown, 51KO MEFs with FKBP51 re-expression rescue, adipogenic gene expression, fatty acid synthase activity, p38 inhibitor, phospho-site mutants\",\n      \"journal\": \"Molecular endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — KO with genetic rescue, phospho-site mutagenesis, multiple functional assays; mechanistic detail for specific residues\",\n      \"pmids\": [\"24933247\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"FKBP51 associates with BECN1 (Beclin-1), alters its phosphorylation and protein levels, and enhances autophagy markers and autophagic flux. The autophagy-enhancing function of FKBP51 is required for antidepressant action in cells and mice.\",\n      \"method\": \"Co-immunoprecipitation of FKBP51-BECN1, western blot for autophagy markers (LC3-II), autophagic flux assays, FKBP5 KO mice, antidepressant behavioral testing\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, autophagic flux assay, KO mouse behavioral validation; single lab\",\n      \"pmids\": [\"25714272\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"FKBP51 acts as a scaffolding protein enhancing PHLPP-AKT interaction to facilitate PHLPP-mediated dephosphorylation of AKT at Ser473, thereby negatively regulating AKT activation in cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, western blot for AKT phosphorylation, FKBP51 overexpression/knockdown, pancreatic cancer cell lines\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP establishing ternary complex, phosphorylation assay, single lab\",\n      \"pmids\": [\"28363942\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"USP49 deubiquitinates and stabilizes FKBP51, which in turn enhances PHLPP-mediated dephosphorylation of AKT, establishing USP49 as an upstream regulator of the FKBP51-PHLPP-AKT pathway.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, western blot for FKBP51 protein stability and AKT phosphorylation, USP49 overexpression/knockdown in pancreatic cancer cells\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, functional rescue; single lab\",\n      \"pmids\": [\"28363942\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"FKBP51 plays a role in energy and glucose homeostasis: FKBP51 associates with AS160 (a substrate of AKT2 involved in glucose uptake), and FKBP51 antagonism increases phosphorylation of AS160, increases GLUT4 expression at the plasma membrane, and enhances glucose uptake in skeletal myotubes. Fkbp5 KO mice are protected from high-fat diet-induced weight gain and show improved glucose tolerance.\",\n      \"method\": \"Co-immunoprecipitation (FKBP51-AS160), GLUT4 membrane fractionation, glucose uptake assay in myotubes, Fkbp5 KO mouse model, pharmacological inhibition with SAFit2\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP, subcellular fractionation, in vitro functional assay, KO mouse, pharmacological validation; multiple orthogonal methods\",\n      \"pmids\": [\"29170369\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"FKBP51 interacts with DLC1 and DLC2 (Rho GTPase-activating proteins). Overexpression of FKBP51 enhances RhoA activity and Rho-ROCK signaling, promoting cell motility and invasion, while FKBP51 depletion reduces RhoA activity and causes cortical actin redistribution.\",\n      \"method\": \"Immunoprecipitation and mass spectrometry (interactor identification), RhoA activity assay, cell motility/invasion assays, FKBP51 overexpression and knockdown in U2OS cells\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — IP-MS for interactor discovery, RhoA activity assay, functional invasion assay; single lab\",\n      \"pmids\": [\"28032931\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"FKBP51 modulates NF-κB signaling: FKBP51 is present in a complex comprising Hsp90, GR, and members of the IKK family (IKKα/β). FKBP51 silencing reduces NF-κB (p50/p65) nuclear translocation, decreases ICAM expression and cytokine/chemokine secretion, and increases GR sensitivity to glucocorticoids in bronchial epithelial cells.\",\n      \"method\": \"Co-immunoprecipitation (anti-FKBP51 antibody), siRNA silencing, NF-κB nuclear translocation assay, cytokine ELISA, GR reporter assay, FKBP51 overexpression in murine pulmonary inflammation model\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP establishing Hsp90/GR/IKK complex, functional knockdown with multiple readouts; single lab\",\n      \"pmids\": [\"30169894\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"FKBP51 silencing reduces NF-κB signaling and increases GR sensitivity, identifying FKBP51 as a component of the IKK complex that regulates both NF-κB-driven inflammation and glucocorticoid responsiveness.\",\n      \"method\": \"Immunoprecipitation, siRNA, reporter assay, cytokine measurements\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and functional silencing, single lab\",\n      \"pmids\": [\"30169894\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The glucocorticoid receptor (GR) and FKBP51 form a protein complex that is elevated in PTSD patients and in fear-conditioned mice. The GR-FKBP51 complex is associated with decreased GR phosphorylation, decreased nuclear GR, and lower 14-3-3ε expression. A peptide disrupting GR-FKBP51 binding reverses fear conditioning-induced behavioral and molecular changes, including restoring GR phosphorylation, increasing GR-FKBP52 interaction, and promoting GR nuclear translocation.\",\n      \"method\": \"Co-immunoprecipitation in human blood samples and mouse brain tissue, GR phosphorylation western blot, nuclear GR fractionation, peptide-mediated disruption of GR-FKBP51 complex, fear conditioning behavioral assay\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP in human and mouse samples, mechanistic peptide disruption, multiple molecular readouts validated in vivo\",\n      \"pmids\": [\"31929189\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"USP53 deubiquitinates FKBP51, leading to dephosphorylation of AKT1 and inhibition of tumor growth in lung adenocarcinoma, establishing USP53 as another deubiquitinase regulating FKBP51 stability and thus the AKT pathway.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, western blot for AKT phosphorylation, USP53 overexpression/knockdown, in vivo xenograft model\",\n      \"journal\": \"Molecular carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, in vivo tumor model; single lab\",\n      \"pmids\": [\"32511815\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"FKBP5 binds IKKα, which is critical for RIG-I-induced innate immune responses. FKBP5 knockout increases influenza A virus (IAV) infection, demonstrating FKBP5 as a host restriction factor acting through RIG-I-mediated NF-κB signaling.\",\n      \"method\": \"FKBP5 KO cells, Co-immunoprecipitation (FKBP5-IKKα), viral infection assay, NF-κB reporter, ISG expression assay\",\n      \"journal\": \"Viruses\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, KO with functional viral phenotype, NF-κB reporter; single lab\",\n      \"pmids\": [\"32580383\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Mineralocorticoid receptor (MR) binding to the Fkbp5 gene (rather than GR binding) regulates baseline FKBP5 expression in hippocampal neurons. MR-dependent FKBP5 expression modifies GR sensitivity to glucocorticoids. Pharmacological MR inhibition and region-specific MR deletion reduce hippocampal Fkbp5 levels and dampen stress-induced glucocorticoid increase.\",\n      \"method\": \"Biotinylated-oligonucleotide immunoprecipitation (biotin-oligo-IP) in primary hippocampal neurons, pharmacological MR antagonism, conditional MR knockout mice, corticosterone measurements\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct MR-DNA binding assay, conditional KO mouse, pharmacological validation; multiple orthogonal methods in single study\",\n      \"pmids\": [\"34077736\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FKBP5 interacts and colocalizes with HTT (huntingtin) in mouse striatum and cortex. Decreasing FKBP5 levels or activity reduces mutant HTT via increased LC3-II levels and macroautophagic flux, in an MTOR-independent manner. In vivo SAFit2 treatment reduces HTT levels in HD mouse models.\",\n      \"method\": \"Co-immunoprecipitation (FKBP5-HTT), siRNA knockdown, SAFit2 pharmacological inhibition, LC3-II western blot, autophagy flux assay, in vivo mouse models (R6/2, zQ175)\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP establishing interaction, genetic and pharmacological loss-of-function, in vivo validation in two mouse models\",\n      \"pmids\": [\"34024231\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FKBP51 promotes decidualization of human endometrial stromal cells (ESCs) by reducing Ser473 phosphorylation of AKT, which increases FOXO1A expression. FKBP51 shRNA inhibited decidualization markers (IGFBP1, PRL) and was rescued by FKBP51 cDNA re-expression.\",\n      \"method\": \"shRNA knockdown of FKBP51 in primary human ESCs, western blot for p-AKT(S473), RT-PCR for IGFBP1/PRL, AKT activator SC79, cDNA rescue, immunohistochemistry on endometrial tissue microarray\",\n      \"journal\": \"Reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD with rescue, AKT phosphorylation assay, functional decidualization markers; single lab\",\n      \"pmids\": [\"29363568\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FKBP51 binding to progesterone receptor (PR) inhibits PR function. Maternal stress increases uterine FKBP51 expression and nuclear FKBP51-PR binding in decidual cells, causing functional P4 withdrawal and preterm birth. Fkbp5-/- mice are completely resistant to maternal stress-induced preterm birth.\",\n      \"method\": \"Co-immunoprecipitation (FKBP51-PR), Fkbp5 KO mouse model, maternal restraint stress paradigm, gene expression analysis (PR, AKR1C18, Oxtr), immunohistochemistry on human decidua from preterm birth cases\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP, Fkbp5 KO mouse with complete phenotypic rescue, human tissue validation, multiple molecular readouts\",\n      \"pmids\": [\"33836562\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FKBP5 regulates trophoblast function and macrophage polarization via PI3K/AKT signaling (trophoblast) and ROS/NF-κB signaling (macrophages). FKBP5 inhibits HAPLN1 expression through suppression of PI3K/AKT and inhibits trophoblast IL-6 secretion, promoting M1 macrophage polarization. FKBP5 inhibitors improved embryo resorption rate in a mouse miscarriage model.\",\n      \"method\": \"Overexpression/knockdown in trophoblast cell lines and THP-1-derived macrophages, western blot for PI3K/AKT and NF-κB pathway components, cytokine ELISA, mouse miscarriage model with FKBP5 inhibitor\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss/gain-of-function with pathway readouts, in vivo mouse model; single lab\",\n      \"pmids\": [\"37827456\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Loss of FKBP5 in hippocampal neurons reduces long-term potentiation (LTP), decreases excitatory synaptic activity (reduced mEPSC frequency, reduced NMDAR1, NMDAR2B, and AMPAR expression), and increases inhibitory GABAergic signaling (elevated GABA, GAD65 expression, increased mIPSC frequency).\",\n      \"method\": \"Fkbp5 KO mice, electrophysiology (LTP recording, mEPSC, mIPSC), western blot for glutamate and GABA receptor subunits and synthesis enzymes\",\n      \"journal\": \"Neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse with electrophysiological and biochemical phenotyping; single lab\",\n      \"pmids\": [\"30685540\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FKBP51 is phosphorylated, SUMOylated, and acetylated as post-translational modifications that regulate its scaffolding interactions. SUMOylation is required for FKBP51's inhibitory action on GR.\",\n      \"method\": \"Review of biochemical studies including in vitro SUMOylation, Ni2+ affinity pulldown, site-directed mutagenesis from primary literature\",\n      \"journal\": \"Biochemical Society transactions\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — review paper synthesizing PTM data; specific SUMO requirement supported by subsequent experimental work (PMID 35256747)\",\n      \"pmids\": [\"31754722\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Tricyclic antidepressants (particularly clomipramine) inhibit FKBP51 SUMOylation by binding to FKBP51 and preventing its interaction with the SUMO E3 ligase PIAS4. Inhibition of FKBP51 SUMOylation decreases FKBP51 binding to Hsp90 and GR, facilitates FKBP52 recruitment to the GR complex, and enhances GR transcriptional activity.\",\n      \"method\": \"Ni2+ affinity pulldown screening, in vitro SUMOylation assay, co-immunoprecipitation (FKBP51-PIAS4, FKBP51-GR), PIAS4 siRNA in rat primary astrocytes, in vivo clomipramine treatment in mice\",\n      \"journal\": \"Molecular psychiatry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro SUMOylation assay, Co-IP for complex changes, siRNA functional rescue, in vivo mouse validation; multiple orthogonal methods\",\n      \"pmids\": [\"35256747\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"FKBP51 serves as a central scaffold in the mediobasal hypothalamus (MBH) linking the LKB1/AMPK complex to WIPI4 and TSC2 to WIPI3, thereby regulating the balance between autophagy and mTOR signaling in response to metabolic challenges. MBH-specific FKBP51 deletion induces obesity; overexpression protects against high-fat diet-induced obesity.\",\n      \"method\": \"Mass spectrometry-based metabolomics (FKBP51 KO cells), co-immunoprecipitation (FKBP51-LKB1/AMPK-WIPI4; TSC2-WIPI3), stereotaxic viral MBH-specific KO/overexpression, high-fat diet mouse model\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP defining multiprotein complexes, region-specific genetic manipulation, metabolic phenotyping; multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"35263141\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FKBP51 regulates androgen receptor (AR) dimer formation; depletion of FKBP51 reduces AR dimer formation, chromatin binding, and phosphorylation. The PPIase (FK1 domain) activity of FKBP51 is required for AR dimerization and prostate cancer cell growth.\",\n      \"method\": \"FKBP51 depletion by siRNA/shRNA, AR dimerization assay, chromatin immunoprecipitation, cell proliferation assay, FK1 domain inhibitor (FK506), PPIase activity requirement tested with domain mutants\",\n      \"journal\": \"Molecular oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with multiple molecular readouts, domain inhibitor; single lab\",\n      \"pmids\": [\"34057812\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"FKBP51 reduces the stability of ERα (estrogen receptor alpha) in breast cancer cells, reciprocal to FKBP52 which stabilizes ERα. FKBP51 was more abundantly expressed in normal tissues than cancer cells.\",\n      \"method\": \"FKBP51/FKBP52 depletion in breast cancer cell lines, ERα protein stability assay, western blot, co-immunoprecipitation, proliferation assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD with protein stability readout, reciprocal functional comparison; single lab\",\n      \"pmids\": [\"35394865\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FKBP5 facilitates assembly of the IκB kinase (IKK) complex for NF-κB activation. CBD (cannabidiol) directly binds FKBP5 at tyrosine 113 (Y113), stabilizes it, and inhibits IKK complex assembly and NF-κB activation. Y113A mutation of FKBP5 reduces CBD's anti-inflammatory effect.\",\n      \"method\": \"Protein intrinsic fluorescence titration, cellular thermal shift assay (CETSA), Stern-Volmer analysis, protein thermal shift assay, Y113A site-directed mutagenesis, IKK complex Co-IP, NF-κB reporter assay, cytokine measurements, in vivo CCI pain model\",\n      \"journal\": \"Brain, behavior, and immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct binding assay, CETSA target engagement, active-site mutagenesis (Y113A), functional complex assembly assay, in vivo validation\",\n      \"pmids\": [\"37196785\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FKBP5 negatively modulates HIF-1α protein levels in cardiomyocytes by competitively interacting with Hsp90, thereby suppressing NCX1 (Na+/Ca2+-exchanger 1) transcription and preventing atrial arrhythmogenesis. Cardiomyocyte-specific FKBP5 knockdown increases HIF-1α, NCX1, action potential alternans, and spontaneous Ca2+ waves.\",\n      \"method\": \"Cardiomyocyte-specific Fkbp5 knockdown mouse (Myh6-Cre), echocardiography, intracardiac stimulation, optical mapping, patch-clamp electrophysiology, Co-immunoprecipitation (FKBP5-Hsp90-HIF-1α), Hsp90 inhibitor (17-AAG) rescue\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with electrophysiological phenotype, Co-IP, pharmacological rescue, human atrial tissue validation; multiple orthogonal methods\",\n      \"pmids\": [\"37154033\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FKBP5 regulates FOXO1 phosphorylation at Serine 256 in pancreatic β-cells. FKBP5 inhibition (siRNA or SAFit2) under inflammatory stress promotes β-cell survival, improves insulin secretion, and upregulates MAFA and NKX6.1. Silencing of FOXO1 abolishes the protective effect of FKBP5 inhibition.\",\n      \"method\": \"siRNA knockdown, SAFit2 pharmacological inhibition, western blot for FOXO1-pS256 and AKT signaling, insulin secretion assay, FOXO1 siRNA epistasis, human and mouse primary islets\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis experiment (FOXO1 KD reversal), phospho-site western blot, primary human islet validation; single lab\",\n      \"pmids\": [\"37452039\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FKBP5 activates mitophagy in oligodendrocytes by ablating PPAR-γ, shaping the remyelination environment. FKBP5 protein levels are elevated in the CNS of cuprizone-treated demyelinated mice and regulate PINK1/Parkin-mediated mitophagy through PPAR-γ.\",\n      \"method\": \"Fkbp5 knockout mice in cuprizone demyelination model, PPAR-γ expression analysis, mitophagy assay (PINK1/Parkin pathway markers), western blot, histology\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse with functional phenotype, pathway marker analysis; single lab\",\n      \"pmids\": [\"37952053\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SIRT1 deacetylates FKBP5 in the BNST, inducing FKBP5 dissociation from the GR, which enhances GR-mediated CRF transcriptional repression and reduces anxiety. SIRT1 directly interacts with and deacetylates FKBP5 as part of this anxiolytic mechanism.\",\n      \"method\": \"Co-immunoprecipitation (SIRT1-FKBP5-GR), site-specific in vivo manipulations (SIRT1 overexpression/pharmacological activation in BNST), CRF expression, electrophysiology, MiniScope calcium imaging, mass spectroscopy\",\n      \"journal\": \"Molecular psychiatry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, in vivo cell-type-specific manipulation, multiple molecular and behavioral readouts; single lab\",\n      \"pmids\": [\"37386058\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FKBP5 levels are inversely correlated with dendritic mushroom spine density and BDNF levels in superficial layer excitatory neurons of the human neocortex (BA11), suggesting FKBP5 impacts synaptic plasticity in a cell-type-specific manner.\",\n      \"method\": \"Single-nucleus RNA sequencing, bulk RNA sequencing, RNAscope, immunohistochemistry, western blot (postmortem human brain n=1024); dendritic spine density measurement\",\n      \"journal\": \"Acta neuropathologica\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — correlational finding in postmortem tissue; no experimental manipulation of FKBP5 to demonstrate causal mechanism\",\n      \"pmids\": [\"36729133\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SKA2 promotes GR signaling by enhancing GR-FKBP4 (FKBP52) interaction, which leads to dissociation of FKBP51 from the GR complex. This mechanism was demonstrated in neurons; SKA2 in CRH+ neurons of the hypothalamic PVN is required for HPA axis responsiveness and negative feedback.\",\n      \"method\": \"In vitro cell-based co-immunoprecipitation assays, conditional neuron-specific SKA2 manipulation (Crh+ neurons), HPA axis responsiveness (corticosterone measurements), postmortem human brain expression\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP establishing GR-FKBP4-FKBP5 complex remodeling, conditional in vivo neuronal manipulation; single lab\",\n      \"pmids\": [\"39705315\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"A V55L missense mutation in FKBP51 enhances AKT phosphorylation and kinase activity. Knock-in mice carrying FKBP51(V55L) show hyperresponsive osteoclast precursors to RANKL, increased osteoclast bone resorption activity, and increased trabecular bone resorption, linked to elevated AKT phosphorylation in bone marrow-derived macrophages.\",\n      \"method\": \"Whole-exome sequencing (mutation identification), FKBP51V55L knock-in transgenic mice, RANKL-stimulated osteoclast differentiation assay, bone resorption assay, western blot for AKT phosphorylation, micro-CT analysis\",\n      \"journal\": \"Experimental & molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function knock-in mice, functional osteoclast assays, AKT pathway readout; single lab\",\n      \"pmids\": [\"28524179\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Fkbp4 (FKBP52) and Fkbp5 (FKBP51) differentially regulate GR nuclear translocation and dynein interaction. In pituitary corticotroph cells, Fkbp5 knockdown further decreases Pomc mRNA levels (i.e., FKBP5 reduces efficiency of glucocorticoid-mediated Pomc suppression), while Fkbp4 knockdown partially cancels dexamethasone-induced Pomc decrease.\",\n      \"method\": \"siRNA knockdown of Fkbp4 and Fkbp5 in AtT-20 corticotroph cells, RT-PCR for Pomc mRNA, western blot for FKBP4/5 protein, dexamethasone treatment\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA epistasis in cell line showing opposing functions of FKBP4 vs FKBP5; single lab\",\n      \"pmids\": [\"34072036\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FKBP51 (encoded by FKBP5) is an Hsp90/Hsp70 co-chaperone and scaffolding immunophilin that acts as a central negative regulator of glucocorticoid receptor (GR) sensitivity by binding the GR-Hsp90 heterocomplex to reduce cortisol affinity and impair nuclear translocation; it is itself transcriptionally induced by GR activation at intronic glucocorticoid response elements (creating an ultra-short negative feedback loop subject to allele-specific, trauma-dependent DNA demethylation), and it regulates multiple additional signaling hubs including the PHLPP-AKT axis (as a scaffold facilitating AKT dephosphorylation), the Akt-p38-PPARγ/GRα phosphorylation axis controlling adipogenesis, GSK3β inhibitory phosphorylation, the IKK/NF-κB complex assembly, Beclin-1-dependent autophagy, WIPI/LKB1-AMPK/mTOR metabolic sensing in the hypothalamus, RhoA-ROCK-mediated cell motility, HIF-1α stability in cardiomyocytes, and androgen receptor dimerization; its activity is regulated post-translationally by SUMOylation (required for GR inhibition, targeted by tricyclic antidepressants via PIAS4), deacetylation by SIRT1, and protein stabilization by deubiquitinases USP49 and USP53.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"FKBP51 (encoded by FKBP5) is an FK506-binding immunophilin that functions principally as an Hsp90 co-chaperone and scaffold controlling steroid hormone receptor signaling and stress physiology [#0, #3]. Originally identified as a peptidyl-prolyl isomerase co-purifying with progesterone receptor complexes [#0], it binds the glucocorticoid receptor (GR)-Hsp90 heterocomplex through its TPR domain, reducing cortisol affinity and impairing GR nuclear translocation [#3, #16]; because FKBP5 is itself transcriptionally induced by activated GR via intronic hormone response elements, it forms an ultra-short negative feedback loop tuning GR sensitivity [#3], and baseline expression is set by mineralocorticoid receptor binding to the gene [#19]. This GR-restraining activity governs HPA-axis stress reactivity in vivo, with Fkbp5 knockout producing antidepressant-like, stress-resistant phenotypes [#5], and a regulatory rs1360780 polymorphism enabling trauma-dependent demethylation of intronic GREs that elevates stress-induced FKBP5 and dysregulates the HPA axis [#6]. FKBP51 also acts reciprocally on other receptors, inhibiting progesterone receptor in decidual cells where maternal-stress-induced FKBP51-PR binding drives preterm birth [#22], and controlling androgen and estrogen receptor function [#28, #29]. Beyond steroid receptors, FKBP51 is a broad signaling scaffold: it chaperones the AKT phosphatase PHLPP to promote AKT(Ser473) dephosphorylation [#10], thereby controlling an Akt-p38-PPAR\\u03b3/GR\\u03b1 axis required for adipogenesis [#7, #8] and influencing glucose homeostasis through AS160/GLUT4 [#12] and FOXO1 in \\u03b2-cells [#32]; it scaffolds GSK3\\u03b2 inhibitory phosphorylation [#4], assembles the IKK complex to drive NF-\\u03baB-dependent inflammation and innate antiviral responses [#14, #18, #30], promotes Beclin-1- and HTT-related autophagy [#9, #20], and links LKB1/AMPK-WIPI and TSC2-WIPI complexes to balance hypothalamic autophagy and mTOR signaling and body weight [#27]. FKBP51 scaffolding is regulated post-translationally: SUMOylation via PIAS4 is required for its GR-inhibitory action and is blocked by tricyclic antidepressants [#26], SIRT1 deacetylation dissociates it from GR [#34], and deubiquitinases USP49 and USP53 stabilize it to sustain the PHLPP-AKT axis [#11, #17].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"Establishing FKBP5 as a distinct immunophilin associated with steroid receptor complexes defined its founding biochemical identity.\",\n      \"evidence\": \"FK506 affinity chromatography and density-gradient analysis of avian progesterone receptor complexes\",\n      \"pmids\": [\"7693698\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional consequence of receptor association defined\", \"Human ortholog and physiology not yet addressed\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Human FKBP51 was shown to inhibit calcineurin in an FK506-dependent manner and to be glucocorticoid-inducible, linking it to immune signaling and steroid responsiveness.\",\n      \"evidence\": \"In vitro calcineurin phosphatase assays, multi-tissue Western blots, and glucocorticoid induction in human T cells\",\n      \"pmids\": [\"9125197\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of induction not mapped\", \"Physiological relevance of calcineurin inhibition unclear\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Domain mapping showed FKBP51 binds calcineurin through its TPR domain independently of FK506/calcium, distinguishing its mode of interaction from FKBP12 and clarifying that it does not regulate NFAT like FKBP12.\",\n      \"evidence\": \"GST pulldowns with purified proteins, deletion-mutant domain mapping, NFAT reporter assays in Jurkat cells\",\n      \"pmids\": [\"11813252\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo significance of calcineurin binding not demonstrated\", \"Did not address GR-complex role\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"FKBP51 was defined as an Hsp90 co-chaperone that reduces GR cortisol affinity and nuclear translocation, and is induced by GR via intronic response elements, establishing the ultra-short negative feedback loop on GR sensitivity.\",\n      \"evidence\": \"Synthesis of GR-chaperone biochemistry, cortisol-binding and induction assays\",\n      \"pmids\": [\"19560279\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Review-level synthesis; structural basis of GR-complex inhibition not resolved here\", \"Quantitative contribution to in vivo HPA tone not defined\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Knockout and Co-IP work tied FKBP5 directly to HPA-axis stress reactivity and to GSK3\\u03b2 regulation, broadening its role from receptor chaperone to stress-circuit and kinase scaffold.\",\n      \"evidence\": \"Fkbp5 KO mice with behavioral and corticosterone phenotyping; Co-IP, domain mapping, and KO validation of GSK3\\u03b2(S9) phosphorylation\",\n      \"pmids\": [\"21935478\", \"25849320\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether GSK3\\u03b2 and HPA effects share a common molecular pathway not resolved\", \"PP2A/CDK5 roles within the heterocomplex not mechanistically dissected\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"A regulatory polymorphism was shown to enable trauma-dependent epigenetic disinhibition of FKBP5, providing a gene-by-environment mechanism for HPA dysregulation.\",\n      \"evidence\": \"3C chromatin conformation capture, bisulfite sequencing of intronic GREs, allele-specific expression in human cohorts and cells\",\n      \"pmids\": [\"23201972\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Causal link from demethylation to specific psychiatric outcomes not established\", \"Tissue-specificity of demethylation incompletely mapped\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"FKBP51 was shown to chaperone the AKT phosphatase PHLPP and to drive an Akt-p38-PPAR\\u03b3/GR\\u03b1 axis essential for adipogenesis, recasting it as a metabolic signaling scaffold acting through specific phospho-residues.\",\n      \"evidence\": \"KO MEFs with re-expression rescue, phospho-site mutants (PPAR\\u03b3 S112, GR\\u03b1 S220/S234), p38 inhibition, reporter and differentiation assays\",\n      \"pmids\": [\"24933248\", \"24933247\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry of the FKBP51-PHLPP-AKT complex not defined\", \"Tissue-level metabolic relevance addressed only in cell models here\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"FKBP51 was linked to Beclin-1-dependent autophagy as a required mediator of antidepressant action, connecting its scaffolding to a degradative pathway.\",\n      \"evidence\": \"FKBP51-BECN1 Co-IP, autophagic flux/LC3-II assays, KO mice with antidepressant behavioral testing\",\n      \"pmids\": [\"25714272\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct effect on Beclin-1 phosphorylation mechanism unresolved\", \"Single-lab Co-IP without reciprocal structural validation\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Cancer studies established FKBP51 as a scaffold enhancing PHLPP-AKT dephosphorylation, stabilized by deubiquitinases, and as a regulator of RhoA-ROCK motility and AKT-dependent glucose uptake, expanding its signaling reach.\",\n      \"evidence\": \"Co-IP and ubiquitination assays (USP49), AKT phospho-readouts in pancreatic cancer; IP-MS and RhoA/invasion assays (DLC1/DLC2); FKBP51-AS160 Co-IP, GLUT4 fractionation, KO-mouse and SAFit2 metabolic phenotyping\",\n      \"pmids\": [\"28363942\", \"28032931\", \"29170369\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct versus indirect nature of some interactions not fully resolved\", \"How a single scaffold coordinates these divergent pathways in vivo unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"FKBP51 was placed within an Hsp90/GR/IKK complex that drives NF-\\u03baB-dependent inflammation while restraining GR sensitivity, coupling immune and glucocorticoid signaling.\",\n      \"evidence\": \"Co-IP, siRNA silencing, NF-\\u03baB translocation and cytokine assays in bronchial epithelial cells; in vivo pulmonary inflammation model\",\n      \"pmids\": [\"30169894\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether FKBP51 directly templates IKK assembly not shown here\", \"Single-lab evidence\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Reciprocal Co-IP in human and mouse defined a GR-FKBP51 complex elevated in PTSD/fear that suppresses GR phosphorylation and nuclear entry and is therapeutically disruptable, while a second study extended FKBP5 to RIG-I-IKK\\u03b1 antiviral restriction and a third identified USP53 as an additional stabilizing deubiquitinase.\",\n      \"evidence\": \"Co-IP in human blood and mouse brain with peptide disruption and fear conditioning; FKBP5-IKK\\u03b1 Co-IP and IAV infection in KO cells; USP53 Co-IP/ubiquitination assay and xenograft\",\n      \"pmids\": [\"31929189\", \"32580383\", \"32511815\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the GR-FKBP51 interface for rational disruption not resolved\", \"Generality of antiviral restriction across viruses untested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Multiple studies broadened FKBP5 control of steroid receptors and tissue physiology: MR sets baseline expression, FKBP51 inhibits PR to drive stress-induced preterm birth, regulates AR dimerization in prostate cancer, ERα stability, hippocampal synaptic plasticity, and decidual/trophoblast function via AKT.\",\n      \"evidence\": \"Biotin-oligo-IP and conditional MR KO; Fkbp5 KO with maternal-stress preterm-birth rescue and human decidua; AR dimerization/ChIP with FK1 inhibitor; ERα stability assays; KO-mouse electrophysiology; ESC shRNA/rescue\",\n      \"pmids\": [\"34077736\", \"33836562\", \"34057812\", \"35394865\", \"30685540\", \"29363568\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How one scaffold selectively tunes opposing steroid receptors not unified\", \"Cell-type determinants of these divergent outcomes unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Post-translational control was mechanistically established: SUMOylation via PIAS4 is required for FKBP51's GR inhibition and is blocked by tricyclic antidepressants, and FKBP51 was defined as a hypothalamic scaffold linking AMPK/WIPI and TSC2/WIPI to balance autophagy and mTOR and control body weight.\",\n      \"evidence\": \"In vitro SUMOylation, Co-IP of complex remodeling, PIAS4 siRNA and in vivo clomipramine; MBH-specific viral KO/overexpression with metabolomics and high-fat-diet phenotyping\",\n      \"pmids\": [\"35256747\", \"35263141\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"SUMO acceptor residues and their structural effect on GR binding not fully mapped here\", \"Interplay between PTMs and scaffolding selectivity unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"A series of studies localized FKBP5 scaffolding to specific tissues and modifications: CBD binding at Y113 blocks IKK assembly, FKBP5-Hsp90 competition limits HIF-1\\u03b1/NCX1 to prevent arrhythmia, SIRT1 deacetylation dissociates FKBP5 from GR, and FKBP5 regulates β-cell FOXO1 and oligodendrocyte mitophagy.\",\n      \"evidence\": \"Direct binding/CETSA and Y113A mutagenesis with IKK Co-IP; cardiomyocyte conditional KO with electrophysiology and Hsp90-HIF-1α Co-IP; SIRT1-FKBP5-GR Co-IP with BNST manipulation; β-cell siRNA/SAFit2 epistasis; cuprizone KO with mitophagy markers\",\n      \"pmids\": [\"37196785\", \"37154033\", \"37386058\", \"37452039\", \"37952053\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether these tissue mechanisms share a common scaffolding module untested\", \"Direct vs indirect engagement of Hsp90 partners in some contexts unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"SKA2 was shown to remodel the GR chaperone complex by promoting GR-FKBP52 interaction and FKBP51 dissociation, identifying an upstream determinant of FKBP51's GR-restraining state in HPA-axis feedback.\",\n      \"evidence\": \"Cell-based Co-IP and conditional CRH-neuron SKA2 manipulation with corticosterone readouts; postmortem human expression\",\n      \"pmids\": [\"39705315\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect SKA2 action on the complex not resolved\", \"Single-lab in vivo evidence\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown how a single immunophilin scaffold achieves selective, tissue-specific control across so many client complexes, and what structural/PTM code dictates whether FKBP51 inhibits or promotes a given receptor or kinase pathway.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified structural model of client selectivity\", \"PTM-to-function mapping incomplete\", \"Causal links from human variants/methylation to disease phenotypes not fully established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [3, 10, 14, 27, 30]},\n      {\"term_id\": \"GO:0044183\", \"supporting_discovery_ids\": [3, 10, 31]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 7, 16, 22]},\n      {\"term_id\": \"GO:0016853\", \"supporting_discovery_ids\": [28]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [3, 10, 14]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [3, 7, 16, 22]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 7, 10, 16]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [14, 18, 30]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [9, 20, 27]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [8, 12, 27, 32]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [3, 5, 6, 16]}\n    ],\n    \"complexes\": [\n      \"GR-Hsp90 heterocomplex\",\n      \"IKK complex\",\n      \"FKBP51-PHLPP-AKT complex\",\n      \"GSK3\\u03b2 heterocomplex\"\n    ],\n    \"partners\": [\n      \"HSP90\",\n      \"NR3C1\",\n      \"PHLPP\",\n      \"AKT1\",\n      \"BECN1\",\n      \"PIAS4\",\n      \"SIRT1\",\n      \"PPP3 (calcineurin)\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}