{"gene":"FKBP8","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":2003,"finding":"FKBP8 (FKBP38) is localized to the outer mitochondrial membrane and functions to anchor Bcl-2 and Bcl-xL to mitochondria, inhibiting apoptosis. FKBP38 co-immunoprecipitates with Bcl-2 and Bcl-xL; dominant-negative mutants or RNAi-mediated depletion causes redistribution of Bcl-2/Bcl-xL away from mitochondria and promotes apoptosis.","method":"Co-immunoprecipitation, dominant-negative overexpression, RNAi, colocalization microscopy","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP and functional validation with dominant-negative mutants and RNAi, replicated across multiple subsequent studies","pmids":["12510191"],"is_preprint":false},{"year":2003,"finding":"FKBP8-mediated cell size reduction downstream of TSC1/TSC2 was demonstrated; antisense knockdown of FKBP38 abolished TSC gene-dependent cell size effects, placing FKBP38 in the TSC/mTOR cell size control pathway.","method":"Antisense knockdown, microarray screen, cell size measurement","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single lab, antisense knockdown with size phenotype readout, consistent with later mTOR inhibitor role","pmids":["12894220"],"is_preprint":false},{"year":2004,"finding":"Loss of FKBP8 in mice causes ectopic, ligand-independent activation of the Sonic hedgehog (SHH) signaling pathway in neural tissues, leading to expansion of ventral cell fates in the posterior neural tube and suppression of eye development, establishing FKBP8 as an essential antagonist of SHH signaling.","method":"Mouse knockout genetic analysis, in vivo neural patterning assays","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic loss-of-function with defined cellular phenotype, replicated in multiple mouse studies","pmids":["15105374"],"is_preprint":false},{"year":2005,"finding":"FKBP38 peptidyl-prolyl cis/trans isomerase (PPIase) activity is constitutively inactive but is activated upon formation of a heterodimeric complex with Ca2+/calmodulin. The activated complex directly binds Bcl-2 via the PPIase active site and regulates Bcl-2 function, promoting apoptosis in neuronal tissues.","method":"Biochemical PPIase activity assay, Ca2+/calmodulin complex formation, RNAi depletion, inhibitor studies","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro enzymatic assay, complex reconstitution, RNAi, and inhibitor pharmacology in multiple orthogonal experiments","pmids":["15990872"],"is_preprint":false},{"year":2005,"finding":"FKBP38 interacts with Bcl-2 through the unstructured flexible loop of Bcl-2 (between helices 1 and 2), and this interaction can regulate phosphorylation within the Bcl-2 loop.","method":"Co-immunoprecipitation, deletion mutant mapping, biochemical interaction assays","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — binding domain mapped by mutant analysis, single lab with two complementary methods","pmids":["15733859"],"is_preprint":false},{"year":2005,"finding":"FKBP38 does not directly inhibit calcineurin activity or physically interact with calcineurin in vitro or in vivo; FKBP38 indirectly affects calcineurin subcellular distribution through interaction with calcineurin ligands such as Bcl-2. This is a NEGATIVE result contradicting the earlier Shirane/Nakayama 2003 calcineurin inhibition claim.","method":"In vitro phosphatase activity assay, co-immunoprecipitation, NFAT reporter assay","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — in vitro assay plus reporter gene analysis, single lab, directly refutes earlier claim","pmids":["15757646"],"is_preprint":false},{"year":2005,"finding":"Presenilins (PS1/2) interact with FKBP38 and form macromolecular complexes with Bcl-2. PS1/2 promote degradation of FKBP38 and Bcl-2 and sequester them in ER/Golgi compartments, thereby inhibiting FKBP38-mediated mitochondrial targeting of Bcl-2 and increasing susceptibility to apoptosis.","method":"Co-immunoprecipitation, subcellular fractionation, pulse-chase, RNAi, knockin mouse neurons","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Co-IP, fractionation, knockin mice), replicated across cell and in vivo models","pmids":["15905180"],"is_preprint":false},{"year":2006,"finding":"FKBP8 specifically interacts with HCV NS5A protein via FKBP8's tetratricopeptide repeat (TPR) domain. FKBP8 forms a ternary complex with Hsp90 and NS5A. siRNA knockdown of FKBP8 suppresses HCV RNA replication in hepatoma cells harboring an HCV replicon.","method":"Co-immunoprecipitation, siRNA knockdown, HCV replicon replication assay","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP mapping interaction domain, functional rescue with siRNA-resistant mutant, replicated by multiple labs","pmids":["17024179"],"is_preprint":false},{"year":2006,"finding":"FKBP38-specific inhibitor DM-CHX inhibits the CaM/Ca2+-activated PPIase activity of FKBP38 with high selectivity (up to 80-fold higher affinity than for FKBP12). Neurotrophic FKBP ligands (GPI1046) preferentially inhibit FKBP38·CaM/Ca2+ over other neuroimmunophilins, linking FKBP38 PPIase inhibition to neuroprotective effects in a rat focal ischemia model.","method":"In vitro PPIase activity assay, competitive inhibition kinetics, rat focal cerebral ischemia model","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro enzymatic assay with defined IC50 values, single lab, in vivo pharmacological validation","pmids":["16547004"],"is_preprint":false},{"year":2006,"finding":"HCV NS5A inhibits apoptosis in Huh7 hepatoma cells specifically through interaction with FKBP38; RNAi depletion of FKBP38 abolishes the anti-apoptotic effect of NS5A. NS5A and FKBP38 co-localize in mitochondria and ER; the BH domain (aa 148-236) of NS5A mediates interaction with FKBP38.","method":"Yeast two-hybrid, in vitro GST pulldown, co-immunoprecipitation, RNAi, apoptosis assay","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid confirmed by in vitro pulldown and Co-IP, functional RNAi, single lab","pmids":["16844119"],"is_preprint":false},{"year":2007,"finding":"FKBP38 is identified as an endogenous inhibitor of mTOR that binds mTOR and inhibits its kinase activity similarly to the FKBP12-rapamycin complex. Rheb (GTP-bound form) directly interacts with FKBP38 and prevents FKBP38 association with mTOR in a GTP-dependent manner, thereby activating mTOR in response to growth factors and nutrients.","method":"Co-immunoprecipitation, in vitro kinase assay, GTPase-binding assay, overexpression/depletion of pathway components","journal":"Science (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro mTOR kinase assay, GTP-dependent protein interaction, replicated and contested by subsequent work","pmids":["17991864"],"is_preprint":false},{"year":2007,"finding":"FKBP8 specifically interacts with the HIF prolyl-4-hydroxylase PHD2 (but not PHD1 or PHD3) through N-terminal regions of both proteins. FKBP38 stabilization of PHD2 requires FKBP38's membrane anchoring; FKBP38 knockdown prolongs PHD2 protein stability, while reconstitution of FKBP38 expression reverses this effect. The PPIase activity of FKBP38 is dispensable for PHD2 regulation.","method":"Yeast two-hybrid, GST pulldown, co-immunoprecipitation, RNAi stable depletion with reconstitution, colocalization, cycloheximide chase","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal binding assays, RNAi plus reconstitution, domain mapping, single lab","pmids":["17353276"],"is_preprint":false},{"year":2007,"finding":"FKBP38 interacts via its three tandem TPR domains with the 26S proteasome (specifically with the S4 subunit of the 19S regulatory particle), anchoring the proteasome to the outer mitochondrial/ER membrane. Fkbp38-/- mouse embryonic fibroblasts show markedly reduced proteasome abundance and activity in membrane fractions.","method":"Immunoprecipitation/mass spectrometry, in vitro binding assay, Fkbp38 knockout MEFs, immunofluorescence","journal":"Genes to cells : devoted to molecular & cellular mechanisms","confidence":"High","confidence_rationale":"Tier 2 / Strong — MS-based interactome confirmed by in vitro direct binding, knockout cells with quantitative proteasome activity assay","pmids":["17573772"],"is_preprint":false},{"year":2007,"finding":"FKBP38 promotes HERG potassium channel trafficking and maturation; FKBP38 co-immunoprecipitates and co-localizes with HERG, and siRNA knockdown of FKBP38 reduces HERG trafficking, while FKBP38 overexpression partially rescues a trafficking-deficient LQT2 mutant (F805C).","method":"Co-immunoprecipitation, siRNA knockdown, overexpression rescue, colocalization microscopy","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, siRNA, and rescue experiment, single lab","pmids":["17569659"],"is_preprint":false},{"year":2007,"finding":"The TPR domain of FKBP38 interacts with the C-terminal domain of Hsp90, but only after FKBP38 has formed a complex with CaM-Ca2+. In the ternary Hsp90-FKBP38-CaM-Ca2+ complex, the active site of FKBP38 is blocked, preventing interaction with Bcl-2. Hsp90 thus acts as a negative regulator of FKBP38 pro-apoptotic activity.","method":"Co-immunoprecipitation, in vitro binding assays, PPIase activity assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro PPIase activity assay demonstrating blockade, Co-IP confirming ternary complex, single lab multiple methods","pmids":["17379601"],"is_preprint":false},{"year":2007,"finding":"CaM-Ca2+ activation of FKBP38 involves two distinct interaction sites: the C-terminal CaM-binding motif (residues Ser290-Asn313) binds the C-terminal CaM lobe in a Ca2+-dependent manner, while the N-terminal CaM lobe interacts with the catalytic FKBP38 domain in a Ca2+-independent manner; only the latter interaction activates FKBP38's enzymatic activity.","method":"NMR chemical shift perturbation, fluorescence spectroscopy, domain deletion mutants","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR structural mapping plus biochemical validation, single lab, multiple orthogonal methods","pmids":["17942410"],"is_preprint":false},{"year":2007,"finding":"Hsp90 increases cell survival of neuroblastoma cells after apoptosis induction in a manner dependent on FKBP38; siRNA depletion of FKBP38 significantly reduces the anti-apoptotic effect of Hsp90, establishing that Hsp90 inhibits FKBP38-mediated pro-apoptotic activity in neuroblastoma cells.","method":"siRNA knockdown, apoptosis assays in neuroblastoma cells","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA epistasis experiment, cell survival readout, consistent with in vitro Hsp90-FKBP38 complex data","pmids":["18036348"],"is_preprint":false},{"year":2008,"finding":"HCV NS5A amino acid Val121 (conserved among all HCV genotypes) is a critical determinant for specific interaction with FKBP38; V121A substitution drastically impairs HCV replicon replication, and revertants restore Val121. FKBP8 partially co-localizes with NS5A in the cytoplasmic membranous web by correlative fluorescence-electron microscopy.","method":"Surface plasmon resonance (Kd = 82 nM), mutational analysis of NS5A, HCV replicon replication assay, correlative fluorescence-EM","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — SPR quantitative binding, mutational rescue in viral replication assay, structural localization by EM","pmids":["18216108"],"is_preprint":false},{"year":2008,"finding":"FKBP8 disruption in mice activates Shh signaling cell-autonomously at a step downstream of Smoothened but upstream of Gli2 transcription factor, and this activation requires the kinesin-2 subunit Kif3a (IFT machinery/cilia). FKBP8 also indirectly promotes BMP signaling through its antagonism of Shh signaling.","method":"Genetic epistasis (double mutant analysis), mouse knockout, mosaic analysis","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with multiple double-mutant combinations placing FKBP8 at a defined pathway position, in vivo","pmids":["18590716"],"is_preprint":false},{"year":2008,"finding":"Fkbp38-/- mice exhibit spina bifida, disorganized neuroepithelium, increased apoptosis, and abnormal nerve fiber extension. FKBP38 interacts with protrudin (a membrane trafficking regulator), and protrudin is hyperphosphorylated in Fkbp38-/- brains, suggesting FKBP38 regulates protrudin-dependent membrane recycling and neurite outgrowth.","method":"Mouse knockout, yeast two-hybrid, phosphorylation analysis, histology","journal":"Genes to cells : devoted to molecular & cellular mechanisms","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockout phenotype plus yeast two-hybrid and phosphorylation analysis, single lab","pmids":["18459960"],"is_preprint":false},{"year":2009,"finding":"Using three different in vitro assays, no interaction between Rheb and FKBP38 was detected, and FKBP38 plays only a very minor role in mTORC1 activation in cell biology experiments. This is a NEGATIVE result directly contradicting the Bai et al. 2007 Science paper.","method":"Multiple in vitro binding assays, cell-based mTORC1 activity assays","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — three independent in vitro assays plus cellular experiments, single lab directly contradicting prior claim","pmids":["19222999"],"is_preprint":false},{"year":2009,"finding":"FKBP38 membrane anchoring via the C-terminal transmembrane domain is required for in cellulo interaction with PHD2 and for regulation of PHD2 protein abundance. FKBP38 mediates proteasomal interaction of PHD2 via a ubiquitin-independent proteasomal pathway. The minimal PHD2-binding domain of FKBP38 is a glutamate-rich sequence at the N-terminus, and PHD2 interacts with the MYND-type Zn2+ finger domain of FKBP38. PHD2 colocalizes with FKBP38 at the ER and mitochondria.","method":"Peptide array binding, fluorescence spectroscopy, FRET, biochemical fractionation, immunofluorescence, domain deletion analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal structural/biochemical methods, domain mapping, mechanistic pathway assignment, single lab","pmids":["19546213"],"is_preprint":false},{"year":2010,"finding":"Rheb regulates FKBP38 interaction with Bcl-2 and Bcl-XL in a GTP-dependent manner in vitro and in response to amino acids and growth factors in cells. GTP-Rheb releases Bcl-XL from FKBP38, enabling Bcl-XL association with pro-apoptotic Bak, making cells more resistant to apoptosis.","method":"In vitro GST pulldown with Rheb variants, co-immunoprecipitation in cells, apoptosis assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro reconstitution plus cellular Co-IP, single lab, extends the Rheb-FKBP38 interaction to Bcl-2 biology","pmids":["20048149"],"is_preprint":false},{"year":2010,"finding":"HCV NS5A disrupts the mTOR-FKBP38 association in a manner dependent on NS5A-FKBP38 interaction, activating mTOR signaling. NS5A-mediated mTOR activation and apoptosis inhibition both require NS5A-FKBP38 binding. GST pulldown and Co-IP confirm NS5A directly competes with mTOR for FKBP38 binding.","method":"GST pulldown, co-immunoprecipitation, mTOR substrate phosphorylation assay, NS5A/FKBP38 mutant analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two binding assays plus functional epistasis using mutants, single lab","pmids":["20439463"],"is_preprint":false},{"year":2010,"finding":"FKBP38 protects Bcl-2 from caspase-3-dependent cleavage by direct interaction through the flexible loop of Bcl-2, which contains the caspase cleavage site. FKBP38 overexpression slows Bcl-2 degradation; knockdown accelerates it; the protective effect is reversed by caspase inhibitors or requires the Bcl-2-binding capacity of FKBP38.","method":"Co-immunoprecipitation, siRNA, cycloheximide chase, caspase inhibitor treatment, FKBP38 binding-defective mutants","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple mutant and inhibitor experiments in single lab, clear mechanistic model with orthogonal validation","pmids":["20139069"],"is_preprint":false},{"year":2011,"finding":"Phosphatidic acid (PA) activates mTORC1 by competing with FKBP38 for binding to mTOR at a site encompassing the rapamycin-FKBP12 binding domain. PA antagonizes FKBP38 inhibition of mTORC1 kinase activity in vitro and displaces FKBP38 from mTOR in cells. However, FKBP38 removal alone is insufficient to activate mTORC1; PA is additionally required for allosteric activation.","method":"In vitro mTORC1 kinase assay, competitive binding assay, RNAi, PLD1-dependent PA generation assay in cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro kinase reconstitution, competition binding, endogenous PA pathway validation, multiple orthogonal methods","pmids":["21737445"],"is_preprint":false},{"year":2011,"finding":"FKBP38 promotes post-translational folding of CFTR in the ER via its PPIase active site. FKBP38 knockdown increases CFTR protein synthesis but inhibits post-translational folding, reducing steady-state CFTR levels, processing, and cell surface expression. Uncoupling FKBP38 from Hsp90 via TPR domain mutation modestly enhances CFTR maturation.","method":"Steady-state and pulse-chase analyses, siRNA knockdown, PPIase active site mutants, TPR domain mutants, surface electrophysiology","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — pulse-chase mechanistic dissection, multiple domain mutants, functional expression assay, single lab rigorous study","pmids":["22030396"],"is_preprint":false},{"year":2011,"finding":"FKBP38 interacts with and promotes degradation of PRL-3 (phosphatase of regenerating liver-3) via the proteasome pathway. The N-terminal region of FKBP38 is required for PRL-3 binding. FKBP38 overexpression reduces PRL-3 levels, while FKBP38 siRNA increases them.","method":"Yeast two-hybrid, co-immunoprecipitation, siRNA, proteasome inhibitor experiments, overexpression studies","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid confirmed by Co-IP, functional proteasome pathway validated by inhibitor, single lab","pmids":["21320469"],"is_preprint":false},{"year":2012,"finding":"The charge-sensitive β5-α1 loop (Leu90-Ile96) of the FKBP38 catalytic domain, containing Asp92 and Asp94, is primarily responsible for Bcl-2 binding. The corresponding Bcl-2 binding epitope was identified via peptide library assay. Site-directed mutagenesis of key residues verified the electrostatic protein-protein interaction interface.","method":"Heteronuclear NMR spectroscopy, peptide library membrane assay, site-directed mutagenesis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — NMR structural mapping of binding interface confirmed by mutagenesis and peptide assay, single rigorous study","pmids":["22523079"],"is_preprint":false},{"year":2013,"finding":"Ca2+/S100 proteins (S100A1, A2, A6, B, P) directly interact with FKBP8 in a Ca2+-dependent manner and inhibit FKBP8 interactions with both Hsp90 and NS5A, thereby also inhibiting HCV RNA replication. This defines a Ca2+-dependent regulatory mechanism suppressing the HCV NS5A-FKBP8-Hsp90 ternary complex.","method":"GST pulldown, S-tag pulldown, surface plasmon resonance, HCV replicon replication assay","journal":"Liver international : official journal of the International Association for the Study of the Liver","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — in vitro quantitative SPR binding, functional viral replication assay, single lab","pmids":["23522085"],"is_preprint":false},{"year":2014,"finding":"ANKMY2 (a protein with ankyrin repeats and MYND Zn2+ finger) interacts with FKBP38 and acts downstream of FKBP38 in the Shh signaling pathway. Depletion of ANKMY2 decreases Shh signaling, while combined depletion of FKBP38 and ANKMY2 attenuates signaling, placing ANKMY2 downstream of FKBP38 as a positive regulator of Shh signaling.","method":"Proteomics, co-immunoprecipitation, siRNA epistasis in MEFs, zebrafish morpholino knockdown","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteomics-identified interaction confirmed by Co-IP, epistasis in two model organisms, single lab","pmids":["25077969"],"is_preprint":false},{"year":2017,"finding":"FKBP8 acts as a mitophagy receptor that binds LC3A via an N-terminal LIR motif. FKBP8 preferentially and strongly recruits lipidated LC3A to damaged mitochondria in a LIR-dependent manner, inducing Parkin-independent mitophagy when co-expressed with LC3A. Strikingly, FKBP8 escapes mitochondrial degradation during mitophagy by translocating away from mitochondria.","method":"Yeast two-hybrid, in vitro pull-down, in vivo co-immunoprecipitation, LIR mutant analysis, live fluorescence microscopy, mitophagy flux assays","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — yeast two-hybrid confirmed by in vitro and in vivo binding, LIR mutant validation, functional mitophagy assay, single rigorous study","pmids":["28381481"],"is_preprint":false},{"year":2017,"finding":"Crystal structure of the FKBP8 TPR domain in complex with Hsp90 MEEVD-containing peptide reveals carboxylate clamp interactions critical for binding. Interactions upstream of the conserved MEEVD motif are required for tight Hsp90 binding. Mutation of Lys307 (in the carboxylate clamp) completely disrupts Hsp90 interaction. FKBP8 does not bind intact Hsp70. FKBP8-Hsp90 binding does not substantially affect Hsp90 ATPase activity.","method":"X-ray crystallography, mutagenesis, binding assays","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure plus mutagenesis validation, single study","pmids":["28278223"],"is_preprint":false},{"year":2017,"finding":"FKBP8 knockout cardiomyocytes accumulate misfolded protein aggregates and show increased ER stress markers and caspase-12-dependent apoptosis under hemodynamic stress (TAC). FKBP8 is localized to ER and mitochondria in cardiomyocytes, interacting with Hsp90. FKBP8 knockdown had no effect on mitophagy in HEK293 cells or H9c2 myocytes (negative result for mitophagy in cardiac context).","method":"Cardiac-specific Fkbp8 knockout mice, TAC surgery, immunoprecipitation, immunofluorescence, ER stress marker analysis, caspase-12 inhibitor rescue","journal":"Journal of molecular and cellular cardiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cardiac-specific KO with defined phenotype, biochemical Co-IP, inhibitor rescue, single lab","pmids":["29129702"],"is_preprint":false},{"year":2018,"finding":"Signal peptide peptidase (SPP) interacts with and co-localizes with FKBP8 in the ER and mediates intramembrane proteolysis-dependent degradation of FKBP8 in the cytosol via a proteasome pathway, thereby activating mTOR signaling.","method":"SILAC quantitative proteomics, co-immunoprecipitation, cycloheximide chase, proteasome inhibitor experiments, xenograft model","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — SILAC proteomics followed by Co-IP and functional degradation assays, single lab","pmids":["30348988"],"is_preprint":false},{"year":2018,"finding":"FKBP8 negatively regulates innate antiviral RLR-VISA signaling by interacting with VISA (MAVS), RIG-I, and IRF3 during viral infection. FKBP8 overexpression attenuates IFN-β and NF-κB promoter activation and decreases IRF3 dimer formation. FKBP8 inhibits TBK1-IRF3 and VISA-TRAF3 complex formation and promotes polyubiquitination-mediated degradation of TBK1, RIG-I, and TRAF3.","method":"Yeast two-hybrid, co-immunoprecipitation, reporter assays, RNAi, ubiquitination assays","journal":"Journal of medical virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid confirmed by multiple Co-IP experiments, reporter and ubiquitination assays, single lab","pmids":["30267576"],"is_preprint":false},{"year":2019,"finding":"FKBP8 contains both an LIR motif and an LIR motif-like sequence (LIRL) at its N-terminus. The LIRL is essential for mitochondrial fragmentation and for FKBP8 binding to OPA1. FKBP8-induced mitochondrial fragmentation occurs independently of Drp1, FIP200, and BNIP3/NIX but requires OPA1. FKBP8 is recruited to sites of mitochondrial division during iron depletion stress and is required for mitochondrial fragmentation and mitophagy under hypoxic stress.","method":"Cell-based functional screening, FKBP8 knockdown and knockout MEFs, live microscopy, domain mutant analysis (LIR/LIRL), co-immunoprecipitation with OPA1","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — knockout cells across multiple genotypes (Drp1-/-, FIP200-/-, BNIP3/NIX DKO, OPA1-/-) epistasis, domain mutants, single rigorous study","pmids":["31908024"],"is_preprint":false},{"year":2020,"finding":"FKBP8 overexpression decreases lipid content in vitro and in vivo via suppression of the mTOR/P70S6K/SREBPs pathway.","method":"FKBP8 overexpression/knockdown, mTOR substrate phosphorylation assay, lipid content assay, mouse HFD model","journal":"Acta pharmaceutica Sinica. B","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional overexpression and KD with pathway readout, in vitro and in vivo, single lab","pmids":["34900535"],"is_preprint":false},{"year":2020,"finding":"Prohibitin 1 (PHB1) specifically interacts with FKBP8 at mitochondria. PHB1 downregulation reduces FKBP8 levels in the mitochondrial fraction and increases FKBP8-mTOR interaction, linking mitochondrial PHB1 to mTOR pathway regulation via FKBP8 subcellular redistribution.","method":"Immunoprecipitation-mass spectrometry, co-immunoprecipitation, subcellular fractionation, PHB1 knockdown","journal":"Frontiers of medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS-identified interaction confirmed by Co-IP, fractionation analysis, single lab","pmids":["33259040"],"is_preprint":false},{"year":2022,"finding":"FKBP8 interacts with MLCK1 (myosin light chain kinase 1) via FKBP8's PPIase (tacrolimus-binding) domain. FKBP8 knockout or dominant-negative FKBP8 prevents TNF-induced MLCK1 recruitment to cell junctions and barrier loss. Tacrolimus blocks MLCK1-FKBP8 binding and reverses TNF-induced MLCK1 recruitment and barrier loss in vitro and in vivo.","method":"In vitro protein interaction assay, knockout/dominant-negative cell lines, intestinal organoids, mouse model, patient biopsy analysis, tacrolimus pharmacological intervention","journal":"Gut","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro binding, KO and dominant-negative cell lines, in vivo mouse model, clinical patient validation, multiple orthogonal methods","pmids":["35537812"],"is_preprint":false},{"year":2022,"finding":"FKBP8 co-localizes with VPS34 complex members ATG14L and BECN1 and is necessary for VPS34 lipid kinase activity during starvation-induced autophagy. FKBP8 depletion abrogates autophagy activation by starvation; FKBP8 overexpression triggers autophagy. The transmembrane domain of FKBP8 (not the LIR) is required for this function and interaction with the VPS34 complex. FKBP8 is not found in completed autophagosomal vesicles.","method":"FKBP8 knockdown/overexpression, autophagy flux assays, colocalization microscopy, VPS34 activity assay, transmembrane domain mutant","journal":"Biochimica et biophysica acta. Molecular cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional knockdown/OE with enzymatic activity assay and colocalization, domain mutant dissection, single lab","pmids":["35090967"],"is_preprint":false},{"year":2022,"finding":"KDM1A (lysine demethylase 1A) directly interacts with and demethylates FKBP8. Demethylation of FKBP8 by KDM1A enhances FKBP8 ability to stabilize BCL2. KDM1A cytoplasmic localization and stability are promoted by KAT8-mediated acetylation at lysine-117, which promotes FKBP8 demethylation and BCL2 accumulation.","method":"Co-immunoprecipitation, demethylation assay, protein stability assays, cancer cell lines and xenograft models","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, enzymatic demethylation assay, functional rescue experiments, single lab","pmids":["35970393"],"is_preprint":false},{"year":2024,"finding":"FKBP8 is the tethering partner of the ER protein PDZD8 at ER-mitochondria contact sites (MERCS). Identified by unbiased proximity proteomics and validated by CRISPR-Cas9 endogenous tagging, cryo-electron tomography, and CLEM. FKBP8 overexpression narrows the ER-OMM distance; combined deletion of PDZD8 and FKBP8 is required for full loss of MERCS. PDZD8 enhances mitochondrial complexity in a FKBP8-dependent manner.","method":"Proximity proteomics (BioID), CRISPR-Cas9 endogenous tagging, cryo-electron tomography, correlative light-electron microscopy (CLEM), single molecule tracking, FKBP8/PDZD8 knockout analysis","journal":"bioRxiv / Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — cryo-EM structural evidence plus proximity proteomics plus genetic epistasis, multiple orthogonal methods, peer-reviewed version published","pmids":["40246839","38895210"],"is_preprint":false},{"year":2025,"finding":"FKBP8 recruits BLTP1 to ER-mitochondria contact sites via direct interaction, establishing a lipid export pathway from mitochondria. BLTP1 deficiency causes pathological accumulation of phosphatidic acid, phosphatidylglycerol, and cardiolipin, mitochondrial ROS elevation, and apoptosis. Depleting intramitochondrial lipid transfer proteins or CL synthesis enzymes prevents BLTP1-deficiency-induced apoptosis.","method":"Proximity proteomics, co-immunoprecipitation, lipidomics, mitochondrial ROS assay, genetic epistasis with lipid pathway knockdowns","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multi-method including lipidomics and genetic epistasis, preprint not yet peer-reviewed","pmids":[],"is_preprint":true},{"year":2025,"finding":"Phosphomimetic tau (at Ser-396/404 or Thr-231/Ser-235) inhibits oxidative stress-induced mitophagy and causes decreased levels of the mitophagy receptor FKBP8 (but not FUNDC1 or BNIP3) in response to paraquat. FKBP8 is normally trafficked to the ER during oxidative-stress-induced mitophagy, and disease-relevant tau impacts this trafficking, potentially through direct interaction.","method":"Immunoblot, subcellular fractionation, neuronal cell lines with tau mutants, paraquat-induced mitophagy assay","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical fractionation with defined cellular readout, multiple tau mutant comparisons, single lab","pmids":["39752365"],"is_preprint":false},{"year":2026,"finding":"FKBP8 interacts with influenza A virus M2 protein via its TPR domain binding to the LIR sequence of M2 (high-affinity interaction). FKBP8 mediates lysosomal degradation of M2 by recruiting RAB7A and LAMP1 to form a FKBP8-RAB7A-LAMP1-M2 complex, inhibiting viral entry and replication.","method":"Affinity purification-MS, co-immunoprecipitation, FKBP8 overexpression/knockdown/knockout, lysosomal inhibitors (BafA1, CQ), cycloheximide assay, viral replication assays","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS-identified interaction confirmed by Co-IP, mechanistic rescue with lysosomal inhibitors, domain mutants, single lab","pmids":["42212595"],"is_preprint":false},{"year":2024,"finding":"FKBP8 can initiate autophagosome biogenesis via two pathways: recruitment of the FIP200/ULK1 complex OR the WIPI-ATG13 complex, demonstrating hierarchical flexibility in autophagy initiation machinery. This was established by reconstitution experiments comparing FKBP8 with BNIP3/NIX, FUNDC1, BCL2L13, and TEX264.","method":"In vitro autophagy reconstitution, comparison of transmembrane autophagy receptors, genetic dissection of initiation complexes","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with defined pathway components, preprint awaiting peer review","pmids":[],"is_preprint":true},{"year":2025,"finding":"RNF25 E3 ubiquitin ligase mediates ubiquitination and degradation of FKBP8. CircSATB1 acts as a scaffold for the RNF25-FKBP8 complex, facilitating RNF25-mediated ubiquitylation of FKBP8 and its proteasomal degradation, thereby relieving FKBP8's inhibitory effect on mTOR signaling.","method":"Co-immunoprecipitation, ubiquitination assay, proteasome inhibitor experiments, FKBP8 knockdown/rescue","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and ubiquitination assay with defined E3 ligase, single lab","pmids":["39921520"],"is_preprint":false}],"current_model":"FKBP8 (FKBP38) is a multifunctional outer mitochondrial membrane/ER-resident immunophilin with a constitutively inactive PPIase domain that is activated by Ca2+/calmodulin binding; in its activated form it binds and regulates Bcl-2 (promoting apoptosis) but is inhibited by Hsp90, while in its non-activated state it anchors Bcl-2/Bcl-xL to mitochondria to suppress apoptosis; FKBP8 also acts as an endogenous inhibitor of mTORC1 (displaced by phosphatidic acid and contested as a direct Rheb effector), a Parkin-independent mitophagy receptor through an N-terminal LIR motif that preferentially recruits LC3A (escaping lysosomal degradation by translocating to the ER), a regulator of mitochondrial fission via binding OPA1 through a distinct LIRL motif, the ER-mitochondria contact site (MERCS) tethering partner of PDZD8, a co-chaperone promoting folding of membrane proteins (CFTR, HERG, CLC-1) via its PPIase domain and TPR-Hsp90 interactions, an anchor for the 26S proteasome at organellar membranes via its TPR domain, a stabilizer of PHD2 protein via ubiquitin-independent proteasomal targeting, a negative regulator of Shh signaling in neural development (acting downstream of Smoothened and upstream of Gli2/Kif3a), and a platform for HCV NS5A-Hsp90 complex assembly required for viral RNA replication."},"narrative":{"mechanistic_narrative":"FKBP8 (FKBP38) is a tail-anchored immunophilin of the outer mitochondrial membrane and ER that integrates apoptosis, organelle dynamics, autophagy, and growth signaling through a modular architecture of an FKBP-type PPIase domain, tandem TPR repeats, and an N-terminal LIR/LIRL region [PMID:12510191, PMID:15990872, PMID:28381481]. Its peptidyl-prolyl isomerase activity is constitutively silent and switched on only upon heterodimerization with Ca2+/calmodulin, whereupon the activated enzyme binds Bcl-2 through a charged loop of its catalytic domain to promote apoptosis, an activity opposed by Hsp90, which binds the TPR domain via a MEEVD carboxylate clamp once the CaM-Ca2+ complex has formed and blocks the active site [PMID:15990872, PMID:17379601, PMID:17942410, PMID:22523079, PMID:28278223]. In its non-activated state FKBP8 instead anchors Bcl-2/Bcl-xL to mitochondria to restrain apoptosis and protects Bcl-2 from caspase-3 cleavage, and this anti-apoptotic tethering is released by GTP-loaded Rheb [PMID:12510191, PMID:20048149, PMID:20139069]. FKBP8 functions as an endogenous mTOR inhibitor by binding mTOR at the rapamycin-FKBP12 site; this inhibition is relieved by phosphatidic acid, which both displaces FKBP8 and allosterically activates the kinase, and the FKBP8–mTOR set point is tuned by its regulated turnover through signal peptide peptidase, RNF25/circSATB1, and ANKMY2/PHB1-dependent relocalization [PMID:17991864, PMID:21737445, PMID:30348988, PMID:33259040, PMID:39921520]. At ER–mitochondria contact sites FKBP8 serves as the OMM tether for the ER protein PDZD8 and recruits the lipid-transfer protein BLTP1, governing contact-site architecture and mitochondrial lipid handling [PMID:40246839, PMID:38895210]. Through its N-terminal LIR motif FKBP8 acts as a Parkin-independent mitophagy receptor that preferentially recruits LC3A and escapes degradation by translocating to the ER, while a distinct LIRL motif drives OPA1-dependent mitochondrial fragmentation, and its transmembrane domain supports VPS34-complex-dependent autophagy initiation [PMID:28381481, PMID:31908024, PMID:35090967]. The TPR and PPIase domains additionally make FKBP8 a co-chaperone and quality-control hub: it promotes folding and trafficking of membrane proteins including CFTR and HERG, anchors the 26S proteasome to organellar membranes, stabilizes or destabilizes specific clients such as PHD2 and PRL-3, and is co-opted by viruses—assembling an Hsp90–NS5A complex required for HCV replication and targeting influenza M2 for lysosomal degradation [PMID:17024179, PMID:17353276, PMID:17573772, PMID:17569659, PMID:22030396, PMID:21320469, PMID:42212595]. In vivo, FKBP8 is an essential cell-autonomous antagonist of Sonic hedgehog signaling acting downstream of Smoothened and upstream of Gli2, with loss causing neural tube and eye patterning defects [PMID:15105374, PMID:18590716, PMID:25077969].","teleology":[{"year":2003,"claim":"Established the founding biological role of FKBP8 by showing it anchors anti-apoptotic Bcl-2/Bcl-xL to the mitochondrial surface, defining it as an apoptosis regulator rather than a generic immunophilin.","evidence":"Co-IP, dominant-negative and RNAi loss-of-function with colocalization in mammalian cells","pmids":["12510191"],"confidence":"High","gaps":["Did not resolve how the interaction is regulated","No structural basis for Bcl-2 binding"]},{"year":2004,"claim":"Revealed an unexpected developmental function by genetic knockout, placing FKBP8 as an essential antagonist of Sonic hedgehog signaling in neural patterning.","evidence":"Mouse knockout and in vivo neural tube patterning analysis","pmids":["15105374"],"confidence":"High","gaps":["Molecular step in the Shh pathway not defined","Relationship to mitochondrial Bcl-2 function unclear"]},{"year":2005,"claim":"Solved how a constitutively inactive PPIase is activated, showing Ca2+/calmodulin binding switches on enzymatic activity that then directly engages Bcl-2 to promote apoptosis.","evidence":"In vitro PPIase assays, CaM-Ca2+ complex reconstitution, RNAi and inhibitor studies","pmids":["15990872","15733859"],"confidence":"High","gaps":["Physiological trigger of Ca2+/CaM activation in cells not defined","How activation toggles between anti- and pro-apoptotic outputs unresolved"]},{"year":2005,"claim":"Refuted the earlier calcineurin-inhibition model and clarified that effects on calcineurin are indirect via Bcl-2, and showed presenilins regulate FKBP8/Bcl-2 stability and localization.","evidence":"In vitro phosphatase and NFAT reporter assays (negative); Co-IP, fractionation and knockin neurons","pmids":["15757646","15905180"],"confidence":"Medium","gaps":["Negative calcineurin result from a single lab","Mechanism of presenilin-driven degradation not detailed"]},{"year":2006,"claim":"Defined FKBP8 as a host co-factor for HCV, showing its TPR domain assembles an Hsp90-NS5A ternary complex required for viral RNA replication and NS5A-mediated apoptosis suppression.","evidence":"Co-IP, siRNA, HCV replicon assays and yeast two-hybrid in hepatoma cells","pmids":["17024179","16844119"],"confidence":"High","gaps":["How NS5A binding alters FKBP8 chaperone function not resolved","Quantitative affinity not yet measured at this stage"]},{"year":2007,"claim":"Proposed FKBP8 as the endogenous mTOR inhibitor displaced by GTP-Rheb, providing a candidate molecular link between Rheb and mTORC1 activation by nutrients and growth factors.","evidence":"Co-IP, in vitro mTOR kinase assay, GTP-dependent binding assays","pmids":["17991864"],"confidence":"High","gaps":["Rheb-FKBP8 interaction subsequently contested","Stoichiometry and structural basis of mTOR inhibition unknown"]},{"year":2007,"claim":"Expanded the chaperone/quality-control repertoire by showing membrane-anchored FKBP8 stabilizes PHD2 via ubiquitin-independent proteasomal targeting, anchors the 26S proteasome to organelle membranes through its TPR domain, and promotes HERG channel trafficking.","evidence":"Y2H, GST pulldown, RNAi-plus-reconstitution, IP-MS, knockout MEFs, CHX chase and rescue assays","pmids":["17353276","17573772","17569659"],"confidence":"High","gaps":["How a single protein both stabilizes and destabilizes clients not mechanistically unified","PPIase dispensability for PHD2 vs requirement for channel folding not reconciled"]},{"year":2007,"claim":"Defined the structural logic of Hsp90 regulation, showing Hsp90 binds the TPR domain only after CaM-Ca2+ binding and thereby blocks the PPIase active site to suppress pro-apoptotic activity, and mapped the CaM activation interface.","evidence":"Co-IP, in vitro binding and PPIase assays, NMR chemical shift perturbation, siRNA epistasis in neuroblastoma","pmids":["17379601","17942410","18036348"],"confidence":"High","gaps":["In vivo balance of Hsp90 vs CaM occupancy not quantified","Cell-type specificity of the apoptotic switch unclear"]},{"year":2008,"claim":"Positioned FKBP8 precisely in the Shh pathway by genetic epistasis, acting downstream of Smoothened, upstream of Gli2 and dependent on the ciliary IFT subunit Kif3a, and linked loss to neural tube defects via protrudin.","evidence":"Mouse double-mutant epistasis, mosaic analysis, Y2H, phosphorylation analysis; SPR (Kd 82 nM) for NS5A and correlative fluorescence-EM","pmids":["18590716","18216108","18459960"],"confidence":"High","gaps":["Direct molecular target of FKBP8 within the Shh/cilia axis not identified","Link between mitochondrial localization and ciliary signaling unexplained"]},{"year":2009,"claim":"Challenged the Rheb-effector model by failing to detect Rheb-FKBP8 interaction in three assays and assigning only a minor role to FKBP8 in mTORC1 activation.","evidence":"Multiple in vitro binding assays and cell-based mTORC1 activity assays (negative result)","pmids":["19222999"],"confidence":"Medium","gaps":["Discrepancy with prior Science report not resolved","Single lab, conditions may differ from original study"]},{"year":2010,"claim":"Extended Rheb regulation to apoptosis and HCV biology, showing GTP-Rheb releases Bcl-xL from FKBP8, NS5A competes with mTOR for FKBP8 binding to activate mTOR, and FKBP8 protects Bcl-2 from caspase cleavage.","evidence":"GST pulldown, Co-IP, mTOR substrate phosphorylation, apoptosis and CHX-chase assays with binding-defective mutants","pmids":["20048149","20439463","20139069"],"confidence":"Medium","gaps":["Reconciliation with the negative Rheb result still open","Quantitative contribution to physiological mTOR control unknown"]},{"year":2011,"claim":"Resolved part of the mTOR controversy by showing phosphatidic acid both displaces FKBP8 from mTOR and provides additional allosteric activation, and defined FKBP8 as a PPIase-dependent folding co-chaperone for CFTR.","evidence":"In vitro mTORC1 kinase and competition assays, PLD1/PA pathway validation; pulse-chase, PPIase and TPR mutants, surface electrophysiology","pmids":["21737445","22030396","21320469"],"confidence":"High","gaps":["How PA-mediated displacement integrates with Rheb signaling unclear","PRL-3 degradation mechanism less defined"]},{"year":2012,"claim":"Provided atomic-level definition of the Bcl-2 interface, identifying the charge-sensitive beta5-alpha1 loop of the catalytic domain as the electrostatic Bcl-2 binding determinant.","evidence":"Heteronuclear NMR, peptide library assay, site-directed mutagenesis","pmids":["22523079"],"confidence":"High","gaps":["Structure of the full FKBP8-Bcl-2 complex not solved","Relationship of this interface to PPIase catalysis not addressed"]},{"year":2013,"claim":"Identified a Ca2+/S100-dependent brake on the HCV complex, showing S100 proteins bind FKBP8 and disrupt both Hsp90 and NS5A interactions to suppress viral replication.","evidence":"GST/S-tag pulldown, SPR, HCV replicon replication assay","pmids":["23522085"],"confidence":"Medium","gaps":["Physiological S100 levels needed for regulation unknown","Overlap with CaM regulation of the same surface not dissected"]},{"year":2017,"claim":"Recast FKBP8 as a Parkin-independent mitophagy receptor with an N-terminal LIR that preferentially recruits LC3A and a unique ability to escape degradation by translocating to the ER, and defined the TPR-Hsp90 MEEVD carboxylate-clamp interface structurally.","evidence":"Y2H, in vitro/in vivo pulldowns, LIR mutants, mitophagy flux assays; X-ray crystallography with MEEVD peptide and mutagenesis","pmids":["28381481","28278223"],"confidence":"High","gaps":["Trigger and machinery for ER translocation not defined","Physiological mitophagy contribution debated across cell types"]},{"year":2017,"claim":"Demonstrated an ER-stress protective role in heart, showing cardiac FKBP8 loss causes protein aggregation and caspase-12-dependent apoptosis, while finding no mitophagy role in this context.","evidence":"Cardiac-specific knockout mice with TAC, IP, ER stress markers, caspase-12 inhibitor rescue (negative for mitophagy)","pmids":["29129702"],"confidence":"Medium","gaps":["Cell-type basis for absent mitophagy not explained","Direct misfolded clients in cardiomyocytes not identified"]},{"year":2018,"claim":"Identified regulated FKBP8 turnover as a control node for mTOR and innate immunity, with signal peptide peptidase mediating its intramembrane proteolysis and FKBP8 negatively regulating RLR-VISA antiviral signaling.","evidence":"SILAC proteomics, Co-IP, CHX chase, proteasome inhibitors, xenograft; Y2H, reporter and ubiquitination assays","pmids":["30348988","30267576"],"confidence":"Medium","gaps":["Physiological stimuli driving SPP cleavage unknown","Direct vs indirect effects on RLR components not fully separated"]},{"year":2019,"claim":"Distinguished a second N-terminal motif, the LIRL, as the OPA1-binding element driving Drp1-independent mitochondrial fragmentation under iron-depletion and hypoxic stress, separating fission from canonical LIR-mediated mitophagy.","evidence":"Functional screening, knockout MEF epistasis (Drp1, FIP200, BNIP3/NIX, OPA1), domain mutants, Co-IP with OPA1","pmids":["31908024"],"confidence":"High","gaps":["Mechanism by which FKBP8-OPA1 binding promotes fission unclear","How LIR and LIRL functions are coordinated unknown"]},{"year":2020,"claim":"Connected FKBP8 to lipid metabolism and uncovered upstream localization control, with FKBP8 suppressing the mTOR/P70S6K/SREBP lipogenic axis and PHB1 governing its mitochondrial pool and mTOR association.","evidence":"Overexpression/knockdown with pathway readouts and HFD model; IP-MS, Co-IP and fractionation with PHB1 knockdown","pmids":["34900535","33259040"],"confidence":"Medium","gaps":["Direct mechanism of lipid reduction beyond mTOR not defined","How PHB1 controls FKBP8 distribution mechanistically unknown"]},{"year":2022,"claim":"Diversified FKBP8 functions into autophagy initiation, epithelial barrier control and epigenetic regulation of Bcl-2 stability, including a PPIase-dependent MLCK1 interaction targetable by tacrolimus.","evidence":"VPS34 activity and autophagy flux assays with TM-domain mutants; in vitro binding, KO/dominant-negative cells, organoids, mouse and patient biopsies; demethylation and stability assays for KDM1A","pmids":["35090967","35537812","35970393"],"confidence":"High","gaps":["How the same protein selects between LIR-driven mitophagy and TM-driven VPS34 autophagy unresolved","In vivo relevance of KDM1A-FKBP8 axis limited to cancer models"]},{"year":2024,"claim":"Established FKBP8 as the OMM tether for PDZD8 at ER-mitochondria contact sites, providing structural evidence that FKBP8 shapes contact-site architecture and mitochondrial morphology.","evidence":"BioID proximity proteomics, CRISPR endogenous tagging, cryo-electron tomography, CLEM and knockout epistasis","pmids":["40246839","38895210"],"confidence":"High","gaps":["Functional output of PDZD8-FKBP8 tethering beyond morphology not fully defined","How tethering integrates with apoptotic and autophagic roles unknown"]},{"year":2025,"claim":"Linked FKBP8 contact-site tethering to lipid transport and turnover control, recruiting BLTP1 for mitochondrial lipid export and being degraded by RNF25/circSATB1 to relieve mTOR inhibition.","evidence":"Proximity proteomics, Co-IP, lipidomics, ROS and epistasis assays (preprint); Co-IP, ubiquitination and proteasome-inhibitor assays for RNF25","pmids":["39921520"],"confidence":"Medium","gaps":["BLTP1 lipid-export finding is a preprint awaiting peer review","Directionality and selectivity of lipid transfer not fully established"]},{"year":2026,"claim":"Showed FKBP8 acts as an antiviral restriction factor against influenza A, using its TPR domain to bind M2 LIR and recruiting RAB7A/LAMP1 to drive lysosomal degradation of M2.","evidence":"AP-MS, Co-IP, overexpression/knockdown/knockout, lysosomal inhibitors, CHX chase and viral replication assays","pmids":["42212595"],"confidence":"Medium","gaps":["Contrast with FKBP8's pro-viral HCV role not mechanistically reconciled","Single-lab finding without independent replication"]},{"year":null,"claim":"How FKBP8 selects among its many mutually exclusive functions—pro- vs anti-apoptotic, mitophagy vs fission vs contact-site tethering, mTOR inhibition vs chaperone activity—through domain occupancy, localization and post-translational control remains the central open question.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking domain state to functional output","In vivo physiological hierarchy of competing roles undetermined","Structural basis of the apoptotic switch in a cellular context unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016853","term_label":"isomerase activity","supporting_discovery_ids":[3,15,26]},{"term_id":"GO:0044183","term_label":"protein folding chaperone","supporting_discovery_ids":[26,13,11]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[10,25,0]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[31,42,12]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[26]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0,36,42]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[21,26,33]}],"pathway":[{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[0,3,24]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[31,40,36]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[10,25,2]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[26,12,11]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[2,18]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[7,45,35]}],"complexes":["FKBP8-CaM/Ca2+ complex","Hsp90-FKBP8-NS5A ternary complex","FKBP8-PDZD8 ER-mitochondria tether","26S proteasome (membrane-anchored)"],"partners":["BCL2","HSP90","MTOR","PDZD8","OPA1","PHD2","CALM1","MAP1LC3A"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q14318","full_name":"Peptidyl-prolyl cis-trans isomerase FKBP8","aliases":["38 kDa FK506-binding protein","38 kDa FKBP","FKBP-38","hFKBP38","FK506-binding protein 8","FKBP-8","FKBPR38","Rotamase"],"length_aa":412,"mass_kda":44.6,"function":"Constitutively inactive PPiase, which becomes active when bound to calmodulin and calcium. Seems to act as a chaperone for BCL2, targets it to the mitochondria and modulates its phosphorylation state. The BCL2/FKBP8/calmodulin/calcium complex probably interferes with the binding of BCL2 to its targets. The active form of FKBP8 may therefore play a role in the regulation of apoptosis. Involved in the inhibition of viral infection by influenza A viruses (IAV) (PubMed:28169297)","subcellular_location":"Mitochondrion membrane","url":"https://www.uniprot.org/uniprotkb/Q14318/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/FKBP8","classification":"Not Classified","n_dependent_lines":59,"n_total_lines":1208,"dependency_fraction":0.048841059602649006},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000105701","cell_line_id":"CID001697","localizations":[{"compartment":"mitochondria","grade":3},{"compartment":"cytoplasmic","grade":2}],"interactors":[{"gene":"DAD1","stoichiometry":10.0},{"gene":"OSTC","stoichiometry":10.0},{"gene":"SUGT1","stoichiometry":4.0},{"gene":"STT3B","stoichiometry":4.0},{"gene":"STT3A","stoichiometry":4.0},{"gene":"TOMM40","stoichiometry":4.0},{"gene":"CANX","stoichiometry":0.2},{"gene":"CAPZB","stoichiometry":0.2},{"gene":"DDOST","stoichiometry":0.2},{"gene":"DNAJB6","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001697","total_profiled":1310},"omim":[{"mim_id":"604840","title":"FK506-BINDING PROTEIN 8; FKBP8","url":"https://www.omim.org/entry/604840"},{"mim_id":"604730","title":"TUB-LIKE PROTEIN 3; TULP3","url":"https://www.omim.org/entry/604730"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Mitochondria","reliability":"Supported"},{"location":"Endoplasmic reticulum","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/FKBP8"},"hgnc":{"alias_symbol":["FKBP38","FKBPr38"],"prev_symbol":[]},"alphafold":{"accession":"Q14318","domains":[{"cath_id":"3.10.50.40","chopping":"93-203","consensus_level":"high","plddt":95.5596,"start":93,"end":203},{"cath_id":"1.25.40.10","chopping":"207-302","consensus_level":"medium","plddt":97.3873,"start":207,"end":302},{"cath_id":"1.10.287","chopping":"318-368","consensus_level":"medium","plddt":94.7884,"start":318,"end":368}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q14318","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q14318-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q14318-F1-predicted_aligned_error_v6.png","plddt_mean":80.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=FKBP8","jax_strain_url":"https://www.jax.org/strain/search?query=FKBP8"},"sequence":{"accession":"Q14318","fasta_url":"https://rest.uniprot.org/uniprotkb/Q14318.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q14318/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q14318"}},"corpus_meta":[{"pmid":"28381481","id":"PMC_28381481","title":"FKBP8 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FKBP38 co-immunoprecipitates with Bcl-2 and Bcl-xL; dominant-negative mutants or RNAi-mediated depletion causes redistribution of Bcl-2/Bcl-xL away from mitochondria and promotes apoptosis.\",\n      \"method\": \"Co-immunoprecipitation, dominant-negative overexpression, RNAi, colocalization microscopy\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP and functional validation with dominant-negative mutants and RNAi, replicated across multiple subsequent studies\",\n      \"pmids\": [\"12510191\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"FKBP8-mediated cell size reduction downstream of TSC1/TSC2 was demonstrated; antisense knockdown of FKBP38 abolished TSC gene-dependent cell size effects, placing FKBP38 in the TSC/mTOR cell size control pathway.\",\n      \"method\": \"Antisense knockdown, microarray screen, cell size measurement\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single lab, antisense knockdown with size phenotype readout, consistent with later mTOR inhibitor role\",\n      \"pmids\": [\"12894220\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Loss of FKBP8 in mice causes ectopic, ligand-independent activation of the Sonic hedgehog (SHH) signaling pathway in neural tissues, leading to expansion of ventral cell fates in the posterior neural tube and suppression of eye development, establishing FKBP8 as an essential antagonist of SHH signaling.\",\n      \"method\": \"Mouse knockout genetic analysis, in vivo neural patterning assays\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic loss-of-function with defined cellular phenotype, replicated in multiple mouse studies\",\n      \"pmids\": [\"15105374\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"FKBP38 peptidyl-prolyl cis/trans isomerase (PPIase) activity is constitutively inactive but is activated upon formation of a heterodimeric complex with Ca2+/calmodulin. The activated complex directly binds Bcl-2 via the PPIase active site and regulates Bcl-2 function, promoting apoptosis in neuronal tissues.\",\n      \"method\": \"Biochemical PPIase activity assay, Ca2+/calmodulin complex formation, RNAi depletion, inhibitor studies\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro enzymatic assay, complex reconstitution, RNAi, and inhibitor pharmacology in multiple orthogonal experiments\",\n      \"pmids\": [\"15990872\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"FKBP38 interacts with Bcl-2 through the unstructured flexible loop of Bcl-2 (between helices 1 and 2), and this interaction can regulate phosphorylation within the Bcl-2 loop.\",\n      \"method\": \"Co-immunoprecipitation, deletion mutant mapping, biochemical interaction assays\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — binding domain mapped by mutant analysis, single lab with two complementary methods\",\n      \"pmids\": [\"15733859\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"FKBP38 does not directly inhibit calcineurin activity or physically interact with calcineurin in vitro or in vivo; FKBP38 indirectly affects calcineurin subcellular distribution through interaction with calcineurin ligands such as Bcl-2. This is a NEGATIVE result contradicting the earlier Shirane/Nakayama 2003 calcineurin inhibition claim.\",\n      \"method\": \"In vitro phosphatase activity assay, co-immunoprecipitation, NFAT reporter assay\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro assay plus reporter gene analysis, single lab, directly refutes earlier claim\",\n      \"pmids\": [\"15757646\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Presenilins (PS1/2) interact with FKBP38 and form macromolecular complexes with Bcl-2. PS1/2 promote degradation of FKBP38 and Bcl-2 and sequester them in ER/Golgi compartments, thereby inhibiting FKBP38-mediated mitochondrial targeting of Bcl-2 and increasing susceptibility to apoptosis.\",\n      \"method\": \"Co-immunoprecipitation, subcellular fractionation, pulse-chase, RNAi, knockin mouse neurons\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Co-IP, fractionation, knockin mice), replicated across cell and in vivo models\",\n      \"pmids\": [\"15905180\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"FKBP8 specifically interacts with HCV NS5A protein via FKBP8's tetratricopeptide repeat (TPR) domain. FKBP8 forms a ternary complex with Hsp90 and NS5A. siRNA knockdown of FKBP8 suppresses HCV RNA replication in hepatoma cells harboring an HCV replicon.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, HCV replicon replication assay\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP mapping interaction domain, functional rescue with siRNA-resistant mutant, replicated by multiple labs\",\n      \"pmids\": [\"17024179\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"FKBP38-specific inhibitor DM-CHX inhibits the CaM/Ca2+-activated PPIase activity of FKBP38 with high selectivity (up to 80-fold higher affinity than for FKBP12). Neurotrophic FKBP ligands (GPI1046) preferentially inhibit FKBP38·CaM/Ca2+ over other neuroimmunophilins, linking FKBP38 PPIase inhibition to neuroprotective effects in a rat focal ischemia model.\",\n      \"method\": \"In vitro PPIase activity assay, competitive inhibition kinetics, rat focal cerebral ischemia model\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzymatic assay with defined IC50 values, single lab, in vivo pharmacological validation\",\n      \"pmids\": [\"16547004\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"HCV NS5A inhibits apoptosis in Huh7 hepatoma cells specifically through interaction with FKBP38; RNAi depletion of FKBP38 abolishes the anti-apoptotic effect of NS5A. NS5A and FKBP38 co-localize in mitochondria and ER; the BH domain (aa 148-236) of NS5A mediates interaction with FKBP38.\",\n      \"method\": \"Yeast two-hybrid, in vitro GST pulldown, co-immunoprecipitation, RNAi, apoptosis assay\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid confirmed by in vitro pulldown and Co-IP, functional RNAi, single lab\",\n      \"pmids\": [\"16844119\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"FKBP38 is identified as an endogenous inhibitor of mTOR that binds mTOR and inhibits its kinase activity similarly to the FKBP12-rapamycin complex. Rheb (GTP-bound form) directly interacts with FKBP38 and prevents FKBP38 association with mTOR in a GTP-dependent manner, thereby activating mTOR in response to growth factors and nutrients.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay, GTPase-binding assay, overexpression/depletion of pathway components\",\n      \"journal\": \"Science (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro mTOR kinase assay, GTP-dependent protein interaction, replicated and contested by subsequent work\",\n      \"pmids\": [\"17991864\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"FKBP8 specifically interacts with the HIF prolyl-4-hydroxylase PHD2 (but not PHD1 or PHD3) through N-terminal regions of both proteins. FKBP38 stabilization of PHD2 requires FKBP38's membrane anchoring; FKBP38 knockdown prolongs PHD2 protein stability, while reconstitution of FKBP38 expression reverses this effect. The PPIase activity of FKBP38 is dispensable for PHD2 regulation.\",\n      \"method\": \"Yeast two-hybrid, GST pulldown, co-immunoprecipitation, RNAi stable depletion with reconstitution, colocalization, cycloheximide chase\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal binding assays, RNAi plus reconstitution, domain mapping, single lab\",\n      \"pmids\": [\"17353276\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"FKBP38 interacts via its three tandem TPR domains with the 26S proteasome (specifically with the S4 subunit of the 19S regulatory particle), anchoring the proteasome to the outer mitochondrial/ER membrane. Fkbp38-/- mouse embryonic fibroblasts show markedly reduced proteasome abundance and activity in membrane fractions.\",\n      \"method\": \"Immunoprecipitation/mass spectrometry, in vitro binding assay, Fkbp38 knockout MEFs, immunofluorescence\",\n      \"journal\": \"Genes to cells : devoted to molecular & cellular mechanisms\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — MS-based interactome confirmed by in vitro direct binding, knockout cells with quantitative proteasome activity assay\",\n      \"pmids\": [\"17573772\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"FKBP38 promotes HERG potassium channel trafficking and maturation; FKBP38 co-immunoprecipitates and co-localizes with HERG, and siRNA knockdown of FKBP38 reduces HERG trafficking, while FKBP38 overexpression partially rescues a trafficking-deficient LQT2 mutant (F805C).\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, overexpression rescue, colocalization microscopy\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, siRNA, and rescue experiment, single lab\",\n      \"pmids\": [\"17569659\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"The TPR domain of FKBP38 interacts with the C-terminal domain of Hsp90, but only after FKBP38 has formed a complex with CaM-Ca2+. In the ternary Hsp90-FKBP38-CaM-Ca2+ complex, the active site of FKBP38 is blocked, preventing interaction with Bcl-2. Hsp90 thus acts as a negative regulator of FKBP38 pro-apoptotic activity.\",\n      \"method\": \"Co-immunoprecipitation, in vitro binding assays, PPIase activity assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro PPIase activity assay demonstrating blockade, Co-IP confirming ternary complex, single lab multiple methods\",\n      \"pmids\": [\"17379601\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"CaM-Ca2+ activation of FKBP38 involves two distinct interaction sites: the C-terminal CaM-binding motif (residues Ser290-Asn313) binds the C-terminal CaM lobe in a Ca2+-dependent manner, while the N-terminal CaM lobe interacts with the catalytic FKBP38 domain in a Ca2+-independent manner; only the latter interaction activates FKBP38's enzymatic activity.\",\n      \"method\": \"NMR chemical shift perturbation, fluorescence spectroscopy, domain deletion mutants\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR structural mapping plus biochemical validation, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"17942410\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Hsp90 increases cell survival of neuroblastoma cells after apoptosis induction in a manner dependent on FKBP38; siRNA depletion of FKBP38 significantly reduces the anti-apoptotic effect of Hsp90, establishing that Hsp90 inhibits FKBP38-mediated pro-apoptotic activity in neuroblastoma cells.\",\n      \"method\": \"siRNA knockdown, apoptosis assays in neuroblastoma cells\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA epistasis experiment, cell survival readout, consistent with in vitro Hsp90-FKBP38 complex data\",\n      \"pmids\": [\"18036348\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"HCV NS5A amino acid Val121 (conserved among all HCV genotypes) is a critical determinant for specific interaction with FKBP38; V121A substitution drastically impairs HCV replicon replication, and revertants restore Val121. FKBP8 partially co-localizes with NS5A in the cytoplasmic membranous web by correlative fluorescence-electron microscopy.\",\n      \"method\": \"Surface plasmon resonance (Kd = 82 nM), mutational analysis of NS5A, HCV replicon replication assay, correlative fluorescence-EM\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — SPR quantitative binding, mutational rescue in viral replication assay, structural localization by EM\",\n      \"pmids\": [\"18216108\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"FKBP8 disruption in mice activates Shh signaling cell-autonomously at a step downstream of Smoothened but upstream of Gli2 transcription factor, and this activation requires the kinesin-2 subunit Kif3a (IFT machinery/cilia). FKBP8 also indirectly promotes BMP signaling through its antagonism of Shh signaling.\",\n      \"method\": \"Genetic epistasis (double mutant analysis), mouse knockout, mosaic analysis\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with multiple double-mutant combinations placing FKBP8 at a defined pathway position, in vivo\",\n      \"pmids\": [\"18590716\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Fkbp38-/- mice exhibit spina bifida, disorganized neuroepithelium, increased apoptosis, and abnormal nerve fiber extension. FKBP38 interacts with protrudin (a membrane trafficking regulator), and protrudin is hyperphosphorylated in Fkbp38-/- brains, suggesting FKBP38 regulates protrudin-dependent membrane recycling and neurite outgrowth.\",\n      \"method\": \"Mouse knockout, yeast two-hybrid, phosphorylation analysis, histology\",\n      \"journal\": \"Genes to cells : devoted to molecular & cellular mechanisms\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockout phenotype plus yeast two-hybrid and phosphorylation analysis, single lab\",\n      \"pmids\": [\"18459960\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Using three different in vitro assays, no interaction between Rheb and FKBP38 was detected, and FKBP38 plays only a very minor role in mTORC1 activation in cell biology experiments. This is a NEGATIVE result directly contradicting the Bai et al. 2007 Science paper.\",\n      \"method\": \"Multiple in vitro binding assays, cell-based mTORC1 activity assays\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — three independent in vitro assays plus cellular experiments, single lab directly contradicting prior claim\",\n      \"pmids\": [\"19222999\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"FKBP38 membrane anchoring via the C-terminal transmembrane domain is required for in cellulo interaction with PHD2 and for regulation of PHD2 protein abundance. FKBP38 mediates proteasomal interaction of PHD2 via a ubiquitin-independent proteasomal pathway. The minimal PHD2-binding domain of FKBP38 is a glutamate-rich sequence at the N-terminus, and PHD2 interacts with the MYND-type Zn2+ finger domain of FKBP38. PHD2 colocalizes with FKBP38 at the ER and mitochondria.\",\n      \"method\": \"Peptide array binding, fluorescence spectroscopy, FRET, biochemical fractionation, immunofluorescence, domain deletion analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal structural/biochemical methods, domain mapping, mechanistic pathway assignment, single lab\",\n      \"pmids\": [\"19546213\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Rheb regulates FKBP38 interaction with Bcl-2 and Bcl-XL in a GTP-dependent manner in vitro and in response to amino acids and growth factors in cells. GTP-Rheb releases Bcl-XL from FKBP38, enabling Bcl-XL association with pro-apoptotic Bak, making cells more resistant to apoptosis.\",\n      \"method\": \"In vitro GST pulldown with Rheb variants, co-immunoprecipitation in cells, apoptosis assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro reconstitution plus cellular Co-IP, single lab, extends the Rheb-FKBP38 interaction to Bcl-2 biology\",\n      \"pmids\": [\"20048149\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"HCV NS5A disrupts the mTOR-FKBP38 association in a manner dependent on NS5A-FKBP38 interaction, activating mTOR signaling. NS5A-mediated mTOR activation and apoptosis inhibition both require NS5A-FKBP38 binding. GST pulldown and Co-IP confirm NS5A directly competes with mTOR for FKBP38 binding.\",\n      \"method\": \"GST pulldown, co-immunoprecipitation, mTOR substrate phosphorylation assay, NS5A/FKBP38 mutant analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two binding assays plus functional epistasis using mutants, single lab\",\n      \"pmids\": [\"20439463\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"FKBP38 protects Bcl-2 from caspase-3-dependent cleavage by direct interaction through the flexible loop of Bcl-2, which contains the caspase cleavage site. FKBP38 overexpression slows Bcl-2 degradation; knockdown accelerates it; the protective effect is reversed by caspase inhibitors or requires the Bcl-2-binding capacity of FKBP38.\",\n      \"method\": \"Co-immunoprecipitation, siRNA, cycloheximide chase, caspase inhibitor treatment, FKBP38 binding-defective mutants\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple mutant and inhibitor experiments in single lab, clear mechanistic model with orthogonal validation\",\n      \"pmids\": [\"20139069\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Phosphatidic acid (PA) activates mTORC1 by competing with FKBP38 for binding to mTOR at a site encompassing the rapamycin-FKBP12 binding domain. PA antagonizes FKBP38 inhibition of mTORC1 kinase activity in vitro and displaces FKBP38 from mTOR in cells. However, FKBP38 removal alone is insufficient to activate mTORC1; PA is additionally required for allosteric activation.\",\n      \"method\": \"In vitro mTORC1 kinase assay, competitive binding assay, RNAi, PLD1-dependent PA generation assay in cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro kinase reconstitution, competition binding, endogenous PA pathway validation, multiple orthogonal methods\",\n      \"pmids\": [\"21737445\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"FKBP38 promotes post-translational folding of CFTR in the ER via its PPIase active site. FKBP38 knockdown increases CFTR protein synthesis but inhibits post-translational folding, reducing steady-state CFTR levels, processing, and cell surface expression. Uncoupling FKBP38 from Hsp90 via TPR domain mutation modestly enhances CFTR maturation.\",\n      \"method\": \"Steady-state and pulse-chase analyses, siRNA knockdown, PPIase active site mutants, TPR domain mutants, surface electrophysiology\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — pulse-chase mechanistic dissection, multiple domain mutants, functional expression assay, single lab rigorous study\",\n      \"pmids\": [\"22030396\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"FKBP38 interacts with and promotes degradation of PRL-3 (phosphatase of regenerating liver-3) via the proteasome pathway. The N-terminal region of FKBP38 is required for PRL-3 binding. FKBP38 overexpression reduces PRL-3 levels, while FKBP38 siRNA increases them.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, siRNA, proteasome inhibitor experiments, overexpression studies\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid confirmed by Co-IP, functional proteasome pathway validated by inhibitor, single lab\",\n      \"pmids\": [\"21320469\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The charge-sensitive β5-α1 loop (Leu90-Ile96) of the FKBP38 catalytic domain, containing Asp92 and Asp94, is primarily responsible for Bcl-2 binding. The corresponding Bcl-2 binding epitope was identified via peptide library assay. Site-directed mutagenesis of key residues verified the electrostatic protein-protein interaction interface.\",\n      \"method\": \"Heteronuclear NMR spectroscopy, peptide library membrane assay, site-directed mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — NMR structural mapping of binding interface confirmed by mutagenesis and peptide assay, single rigorous study\",\n      \"pmids\": [\"22523079\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Ca2+/S100 proteins (S100A1, A2, A6, B, P) directly interact with FKBP8 in a Ca2+-dependent manner and inhibit FKBP8 interactions with both Hsp90 and NS5A, thereby also inhibiting HCV RNA replication. This defines a Ca2+-dependent regulatory mechanism suppressing the HCV NS5A-FKBP8-Hsp90 ternary complex.\",\n      \"method\": \"GST pulldown, S-tag pulldown, surface plasmon resonance, HCV replicon replication assay\",\n      \"journal\": \"Liver international : official journal of the International Association for the Study of the Liver\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro quantitative SPR binding, functional viral replication assay, single lab\",\n      \"pmids\": [\"23522085\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"ANKMY2 (a protein with ankyrin repeats and MYND Zn2+ finger) interacts with FKBP38 and acts downstream of FKBP38 in the Shh signaling pathway. Depletion of ANKMY2 decreases Shh signaling, while combined depletion of FKBP38 and ANKMY2 attenuates signaling, placing ANKMY2 downstream of FKBP38 as a positive regulator of Shh signaling.\",\n      \"method\": \"Proteomics, co-immunoprecipitation, siRNA epistasis in MEFs, zebrafish morpholino knockdown\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteomics-identified interaction confirmed by Co-IP, epistasis in two model organisms, single lab\",\n      \"pmids\": [\"25077969\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"FKBP8 acts as a mitophagy receptor that binds LC3A via an N-terminal LIR motif. FKBP8 preferentially and strongly recruits lipidated LC3A to damaged mitochondria in a LIR-dependent manner, inducing Parkin-independent mitophagy when co-expressed with LC3A. Strikingly, FKBP8 escapes mitochondrial degradation during mitophagy by translocating away from mitochondria.\",\n      \"method\": \"Yeast two-hybrid, in vitro pull-down, in vivo co-immunoprecipitation, LIR mutant analysis, live fluorescence microscopy, mitophagy flux assays\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — yeast two-hybrid confirmed by in vitro and in vivo binding, LIR mutant validation, functional mitophagy assay, single rigorous study\",\n      \"pmids\": [\"28381481\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Crystal structure of the FKBP8 TPR domain in complex with Hsp90 MEEVD-containing peptide reveals carboxylate clamp interactions critical for binding. Interactions upstream of the conserved MEEVD motif are required for tight Hsp90 binding. Mutation of Lys307 (in the carboxylate clamp) completely disrupts Hsp90 interaction. FKBP8 does not bind intact Hsp70. FKBP8-Hsp90 binding does not substantially affect Hsp90 ATPase activity.\",\n      \"method\": \"X-ray crystallography, mutagenesis, binding assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure plus mutagenesis validation, single study\",\n      \"pmids\": [\"28278223\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"FKBP8 knockout cardiomyocytes accumulate misfolded protein aggregates and show increased ER stress markers and caspase-12-dependent apoptosis under hemodynamic stress (TAC). FKBP8 is localized to ER and mitochondria in cardiomyocytes, interacting with Hsp90. FKBP8 knockdown had no effect on mitophagy in HEK293 cells or H9c2 myocytes (negative result for mitophagy in cardiac context).\",\n      \"method\": \"Cardiac-specific Fkbp8 knockout mice, TAC surgery, immunoprecipitation, immunofluorescence, ER stress marker analysis, caspase-12 inhibitor rescue\",\n      \"journal\": \"Journal of molecular and cellular cardiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cardiac-specific KO with defined phenotype, biochemical Co-IP, inhibitor rescue, single lab\",\n      \"pmids\": [\"29129702\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Signal peptide peptidase (SPP) interacts with and co-localizes with FKBP8 in the ER and mediates intramembrane proteolysis-dependent degradation of FKBP8 in the cytosol via a proteasome pathway, thereby activating mTOR signaling.\",\n      \"method\": \"SILAC quantitative proteomics, co-immunoprecipitation, cycloheximide chase, proteasome inhibitor experiments, xenograft model\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — SILAC proteomics followed by Co-IP and functional degradation assays, single lab\",\n      \"pmids\": [\"30348988\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"FKBP8 negatively regulates innate antiviral RLR-VISA signaling by interacting with VISA (MAVS), RIG-I, and IRF3 during viral infection. FKBP8 overexpression attenuates IFN-β and NF-κB promoter activation and decreases IRF3 dimer formation. FKBP8 inhibits TBK1-IRF3 and VISA-TRAF3 complex formation and promotes polyubiquitination-mediated degradation of TBK1, RIG-I, and TRAF3.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, reporter assays, RNAi, ubiquitination assays\",\n      \"journal\": \"Journal of medical virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid confirmed by multiple Co-IP experiments, reporter and ubiquitination assays, single lab\",\n      \"pmids\": [\"30267576\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"FKBP8 contains both an LIR motif and an LIR motif-like sequence (LIRL) at its N-terminus. The LIRL is essential for mitochondrial fragmentation and for FKBP8 binding to OPA1. FKBP8-induced mitochondrial fragmentation occurs independently of Drp1, FIP200, and BNIP3/NIX but requires OPA1. FKBP8 is recruited to sites of mitochondrial division during iron depletion stress and is required for mitochondrial fragmentation and mitophagy under hypoxic stress.\",\n      \"method\": \"Cell-based functional screening, FKBP8 knockdown and knockout MEFs, live microscopy, domain mutant analysis (LIR/LIRL), co-immunoprecipitation with OPA1\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — knockout cells across multiple genotypes (Drp1-/-, FIP200-/-, BNIP3/NIX DKO, OPA1-/-) epistasis, domain mutants, single rigorous study\",\n      \"pmids\": [\"31908024\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"FKBP8 overexpression decreases lipid content in vitro and in vivo via suppression of the mTOR/P70S6K/SREBPs pathway.\",\n      \"method\": \"FKBP8 overexpression/knockdown, mTOR substrate phosphorylation assay, lipid content assay, mouse HFD model\",\n      \"journal\": \"Acta pharmaceutica Sinica. B\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional overexpression and KD with pathway readout, in vitro and in vivo, single lab\",\n      \"pmids\": [\"34900535\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Prohibitin 1 (PHB1) specifically interacts with FKBP8 at mitochondria. PHB1 downregulation reduces FKBP8 levels in the mitochondrial fraction and increases FKBP8-mTOR interaction, linking mitochondrial PHB1 to mTOR pathway regulation via FKBP8 subcellular redistribution.\",\n      \"method\": \"Immunoprecipitation-mass spectrometry, co-immunoprecipitation, subcellular fractionation, PHB1 knockdown\",\n      \"journal\": \"Frontiers of medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS-identified interaction confirmed by Co-IP, fractionation analysis, single lab\",\n      \"pmids\": [\"33259040\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"FKBP8 interacts with MLCK1 (myosin light chain kinase 1) via FKBP8's PPIase (tacrolimus-binding) domain. FKBP8 knockout or dominant-negative FKBP8 prevents TNF-induced MLCK1 recruitment to cell junctions and barrier loss. Tacrolimus blocks MLCK1-FKBP8 binding and reverses TNF-induced MLCK1 recruitment and barrier loss in vitro and in vivo.\",\n      \"method\": \"In vitro protein interaction assay, knockout/dominant-negative cell lines, intestinal organoids, mouse model, patient biopsy analysis, tacrolimus pharmacological intervention\",\n      \"journal\": \"Gut\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro binding, KO and dominant-negative cell lines, in vivo mouse model, clinical patient validation, multiple orthogonal methods\",\n      \"pmids\": [\"35537812\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"FKBP8 co-localizes with VPS34 complex members ATG14L and BECN1 and is necessary for VPS34 lipid kinase activity during starvation-induced autophagy. FKBP8 depletion abrogates autophagy activation by starvation; FKBP8 overexpression triggers autophagy. The transmembrane domain of FKBP8 (not the LIR) is required for this function and interaction with the VPS34 complex. FKBP8 is not found in completed autophagosomal vesicles.\",\n      \"method\": \"FKBP8 knockdown/overexpression, autophagy flux assays, colocalization microscopy, VPS34 activity assay, transmembrane domain mutant\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional knockdown/OE with enzymatic activity assay and colocalization, domain mutant dissection, single lab\",\n      \"pmids\": [\"35090967\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"KDM1A (lysine demethylase 1A) directly interacts with and demethylates FKBP8. Demethylation of FKBP8 by KDM1A enhances FKBP8 ability to stabilize BCL2. KDM1A cytoplasmic localization and stability are promoted by KAT8-mediated acetylation at lysine-117, which promotes FKBP8 demethylation and BCL2 accumulation.\",\n      \"method\": \"Co-immunoprecipitation, demethylation assay, protein stability assays, cancer cell lines and xenograft models\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, enzymatic demethylation assay, functional rescue experiments, single lab\",\n      \"pmids\": [\"35970393\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FKBP8 is the tethering partner of the ER protein PDZD8 at ER-mitochondria contact sites (MERCS). Identified by unbiased proximity proteomics and validated by CRISPR-Cas9 endogenous tagging, cryo-electron tomography, and CLEM. FKBP8 overexpression narrows the ER-OMM distance; combined deletion of PDZD8 and FKBP8 is required for full loss of MERCS. PDZD8 enhances mitochondrial complexity in a FKBP8-dependent manner.\",\n      \"method\": \"Proximity proteomics (BioID), CRISPR-Cas9 endogenous tagging, cryo-electron tomography, correlative light-electron microscopy (CLEM), single molecule tracking, FKBP8/PDZD8 knockout analysis\",\n      \"journal\": \"bioRxiv / Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — cryo-EM structural evidence plus proximity proteomics plus genetic epistasis, multiple orthogonal methods, peer-reviewed version published\",\n      \"pmids\": [\"40246839\", \"38895210\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FKBP8 recruits BLTP1 to ER-mitochondria contact sites via direct interaction, establishing a lipid export pathway from mitochondria. BLTP1 deficiency causes pathological accumulation of phosphatidic acid, phosphatidylglycerol, and cardiolipin, mitochondrial ROS elevation, and apoptosis. Depleting intramitochondrial lipid transfer proteins or CL synthesis enzymes prevents BLTP1-deficiency-induced apoptosis.\",\n      \"method\": \"Proximity proteomics, co-immunoprecipitation, lipidomics, mitochondrial ROS assay, genetic epistasis with lipid pathway knockdowns\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multi-method including lipidomics and genetic epistasis, preprint not yet peer-reviewed\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Phosphomimetic tau (at Ser-396/404 or Thr-231/Ser-235) inhibits oxidative stress-induced mitophagy and causes decreased levels of the mitophagy receptor FKBP8 (but not FUNDC1 or BNIP3) in response to paraquat. FKBP8 is normally trafficked to the ER during oxidative-stress-induced mitophagy, and disease-relevant tau impacts this trafficking, potentially through direct interaction.\",\n      \"method\": \"Immunoblot, subcellular fractionation, neuronal cell lines with tau mutants, paraquat-induced mitophagy assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical fractionation with defined cellular readout, multiple tau mutant comparisons, single lab\",\n      \"pmids\": [\"39752365\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"FKBP8 interacts with influenza A virus M2 protein via its TPR domain binding to the LIR sequence of M2 (high-affinity interaction). FKBP8 mediates lysosomal degradation of M2 by recruiting RAB7A and LAMP1 to form a FKBP8-RAB7A-LAMP1-M2 complex, inhibiting viral entry and replication.\",\n      \"method\": \"Affinity purification-MS, co-immunoprecipitation, FKBP8 overexpression/knockdown/knockout, lysosomal inhibitors (BafA1, CQ), cycloheximide assay, viral replication assays\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS-identified interaction confirmed by Co-IP, mechanistic rescue with lysosomal inhibitors, domain mutants, single lab\",\n      \"pmids\": [\"42212595\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FKBP8 can initiate autophagosome biogenesis via two pathways: recruitment of the FIP200/ULK1 complex OR the WIPI-ATG13 complex, demonstrating hierarchical flexibility in autophagy initiation machinery. This was established by reconstitution experiments comparing FKBP8 with BNIP3/NIX, FUNDC1, BCL2L13, and TEX264.\",\n      \"method\": \"In vitro autophagy reconstitution, comparison of transmembrane autophagy receptors, genetic dissection of initiation complexes\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with defined pathway components, preprint awaiting peer review\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RNF25 E3 ubiquitin ligase mediates ubiquitination and degradation of FKBP8. CircSATB1 acts as a scaffold for the RNF25-FKBP8 complex, facilitating RNF25-mediated ubiquitylation of FKBP8 and its proteasomal degradation, thereby relieving FKBP8's inhibitory effect on mTOR signaling.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, proteasome inhibitor experiments, FKBP8 knockdown/rescue\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and ubiquitination assay with defined E3 ligase, single lab\",\n      \"pmids\": [\"39921520\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FKBP8 (FKBP38) is a multifunctional outer mitochondrial membrane/ER-resident immunophilin with a constitutively inactive PPIase domain that is activated by Ca2+/calmodulin binding; in its activated form it binds and regulates Bcl-2 (promoting apoptosis) but is inhibited by Hsp90, while in its non-activated state it anchors Bcl-2/Bcl-xL to mitochondria to suppress apoptosis; FKBP8 also acts as an endogenous inhibitor of mTORC1 (displaced by phosphatidic acid and contested as a direct Rheb effector), a Parkin-independent mitophagy receptor through an N-terminal LIR motif that preferentially recruits LC3A (escaping lysosomal degradation by translocating to the ER), a regulator of mitochondrial fission via binding OPA1 through a distinct LIRL motif, the ER-mitochondria contact site (MERCS) tethering partner of PDZD8, a co-chaperone promoting folding of membrane proteins (CFTR, HERG, CLC-1) via its PPIase domain and TPR-Hsp90 interactions, an anchor for the 26S proteasome at organellar membranes via its TPR domain, a stabilizer of PHD2 protein via ubiquitin-independent proteasomal targeting, a negative regulator of Shh signaling in neural development (acting downstream of Smoothened and upstream of Gli2/Kif3a), and a platform for HCV NS5A-Hsp90 complex assembly required for viral RNA replication.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"FKBP8 (FKBP38) is a tail-anchored immunophilin of the outer mitochondrial membrane and ER that integrates apoptosis, organelle dynamics, autophagy, and growth signaling through a modular architecture of an FKBP-type PPIase domain, tandem TPR repeats, and an N-terminal LIR/LIRL region [#0, #3, #31]. Its peptidyl-prolyl isomerase activity is constitutively silent and switched on only upon heterodimerization with Ca2+/calmodulin, whereupon the activated enzyme binds Bcl-2 through a charged loop of its catalytic domain to promote apoptosis, an activity opposed by Hsp90, which binds the TPR domain via a MEEVD carboxylate clamp once the CaM-Ca2+ complex has formed and blocks the active site [#3, #14, #15, #28, #32]. In its non-activated state FKBP8 instead anchors Bcl-2/Bcl-xL to mitochondria to restrain apoptosis and protects Bcl-2 from caspase-3 cleavage, and this anti-apoptotic tethering is released by GTP-loaded Rheb [#0, #22, #24]. FKBP8 functions as an endogenous mTOR inhibitor by binding mTOR at the rapamycin-FKBP12 site; this inhibition is relieved by phosphatidic acid, which both displaces FKBP8 and allosterically activates the kinase, and the FKBP8–mTOR set point is tuned by its regulated turnover through signal peptide peptidase, RNF25/circSATB1, and ANKMY2/PHB1-dependent relocalization [#10, #25, #34, #38, #47]. At ER–mitochondria contact sites FKBP8 serves as the OMM tether for the ER protein PDZD8 and recruits the lipid-transfer protein BLTP1, governing contact-site architecture and mitochondrial lipid handling [#42, #43]. Through its N-terminal LIR motif FKBP8 acts as a Parkin-independent mitophagy receptor that preferentially recruits LC3A and escapes degradation by translocating to the ER, while a distinct LIRL motif drives OPA1-dependent mitochondrial fragmentation, and its transmembrane domain supports VPS34-complex-dependent autophagy initiation [#31, #36, #40]. The TPR and PPIase domains additionally make FKBP8 a co-chaperone and quality-control hub: it promotes folding and trafficking of membrane proteins including CFTR and HERG, anchors the 26S proteasome to organellar membranes, stabilizes or destabilizes specific clients such as PHD2 and PRL-3, and is co-opted by viruses—assembling an Hsp90–NS5A complex required for HCV replication and targeting influenza M2 for lysosomal degradation [#7, #11, #12, #13, #26, #27, #45]. In vivo, FKBP8 is an essential cell-autonomous antagonist of Sonic hedgehog signaling acting downstream of Smoothened and upstream of Gli2, with loss causing neural tube and eye patterning defects [#2, #18, #30].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Established the founding biological role of FKBP8 by showing it anchors anti-apoptotic Bcl-2/Bcl-xL to the mitochondrial surface, defining it as an apoptosis regulator rather than a generic immunophilin.\",\n      \"evidence\": \"Co-IP, dominant-negative and RNAi loss-of-function with colocalization in mammalian cells\",\n      \"pmids\": [\"12510191\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve how the interaction is regulated\", \"No structural basis for Bcl-2 binding\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Revealed an unexpected developmental function by genetic knockout, placing FKBP8 as an essential antagonist of Sonic hedgehog signaling in neural patterning.\",\n      \"evidence\": \"Mouse knockout and in vivo neural tube patterning analysis\",\n      \"pmids\": [\"15105374\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular step in the Shh pathway not defined\", \"Relationship to mitochondrial Bcl-2 function unclear\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Solved how a constitutively inactive PPIase is activated, showing Ca2+/calmodulin binding switches on enzymatic activity that then directly engages Bcl-2 to promote apoptosis.\",\n      \"evidence\": \"In vitro PPIase assays, CaM-Ca2+ complex reconstitution, RNAi and inhibitor studies\",\n      \"pmids\": [\"15990872\", \"15733859\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological trigger of Ca2+/CaM activation in cells not defined\", \"How activation toggles between anti- and pro-apoptotic outputs unresolved\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Refuted the earlier calcineurin-inhibition model and clarified that effects on calcineurin are indirect via Bcl-2, and showed presenilins regulate FKBP8/Bcl-2 stability and localization.\",\n      \"evidence\": \"In vitro phosphatase and NFAT reporter assays (negative); Co-IP, fractionation and knockin neurons\",\n      \"pmids\": [\"15757646\", \"15905180\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Negative calcineurin result from a single lab\", \"Mechanism of presenilin-driven degradation not detailed\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Defined FKBP8 as a host co-factor for HCV, showing its TPR domain assembles an Hsp90-NS5A ternary complex required for viral RNA replication and NS5A-mediated apoptosis suppression.\",\n      \"evidence\": \"Co-IP, siRNA, HCV replicon assays and yeast two-hybrid in hepatoma cells\",\n      \"pmids\": [\"17024179\", \"16844119\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How NS5A binding alters FKBP8 chaperone function not resolved\", \"Quantitative affinity not yet measured at this stage\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Proposed FKBP8 as the endogenous mTOR inhibitor displaced by GTP-Rheb, providing a candidate molecular link between Rheb and mTORC1 activation by nutrients and growth factors.\",\n      \"evidence\": \"Co-IP, in vitro mTOR kinase assay, GTP-dependent binding assays\",\n      \"pmids\": [\"17991864\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Rheb-FKBP8 interaction subsequently contested\", \"Stoichiometry and structural basis of mTOR inhibition unknown\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Expanded the chaperone/quality-control repertoire by showing membrane-anchored FKBP8 stabilizes PHD2 via ubiquitin-independent proteasomal targeting, anchors the 26S proteasome to organelle membranes through its TPR domain, and promotes HERG channel trafficking.\",\n      \"evidence\": \"Y2H, GST pulldown, RNAi-plus-reconstitution, IP-MS, knockout MEFs, CHX chase and rescue assays\",\n      \"pmids\": [\"17353276\", \"17573772\", \"17569659\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How a single protein both stabilizes and destabilizes clients not mechanistically unified\", \"PPIase dispensability for PHD2 vs requirement for channel folding not reconciled\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Defined the structural logic of Hsp90 regulation, showing Hsp90 binds the TPR domain only after CaM-Ca2+ binding and thereby blocks the PPIase active site to suppress pro-apoptotic activity, and mapped the CaM activation interface.\",\n      \"evidence\": \"Co-IP, in vitro binding and PPIase assays, NMR chemical shift perturbation, siRNA epistasis in neuroblastoma\",\n      \"pmids\": [\"17379601\", \"17942410\", \"18036348\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo balance of Hsp90 vs CaM occupancy not quantified\", \"Cell-type specificity of the apoptotic switch unclear\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Positioned FKBP8 precisely in the Shh pathway by genetic epistasis, acting downstream of Smoothened, upstream of Gli2 and dependent on the ciliary IFT subunit Kif3a, and linked loss to neural tube defects via protrudin.\",\n      \"evidence\": \"Mouse double-mutant epistasis, mosaic analysis, Y2H, phosphorylation analysis; SPR (Kd 82 nM) for NS5A and correlative fluorescence-EM\",\n      \"pmids\": [\"18590716\", \"18216108\", \"18459960\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct molecular target of FKBP8 within the Shh/cilia axis not identified\", \"Link between mitochondrial localization and ciliary signaling unexplained\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Challenged the Rheb-effector model by failing to detect Rheb-FKBP8 interaction in three assays and assigning only a minor role to FKBP8 in mTORC1 activation.\",\n      \"evidence\": \"Multiple in vitro binding assays and cell-based mTORC1 activity assays (negative result)\",\n      \"pmids\": [\"19222999\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Discrepancy with prior Science report not resolved\", \"Single lab, conditions may differ from original study\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Extended Rheb regulation to apoptosis and HCV biology, showing GTP-Rheb releases Bcl-xL from FKBP8, NS5A competes with mTOR for FKBP8 binding to activate mTOR, and FKBP8 protects Bcl-2 from caspase cleavage.\",\n      \"evidence\": \"GST pulldown, Co-IP, mTOR substrate phosphorylation, apoptosis and CHX-chase assays with binding-defective mutants\",\n      \"pmids\": [\"20048149\", \"20439463\", \"20139069\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Reconciliation with the negative Rheb result still open\", \"Quantitative contribution to physiological mTOR control unknown\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Resolved part of the mTOR controversy by showing phosphatidic acid both displaces FKBP8 from mTOR and provides additional allosteric activation, and defined FKBP8 as a PPIase-dependent folding co-chaperone for CFTR.\",\n      \"evidence\": \"In vitro mTORC1 kinase and competition assays, PLD1/PA pathway validation; pulse-chase, PPIase and TPR mutants, surface electrophysiology\",\n      \"pmids\": [\"21737445\", \"22030396\", \"21320469\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How PA-mediated displacement integrates with Rheb signaling unclear\", \"PRL-3 degradation mechanism less defined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Provided atomic-level definition of the Bcl-2 interface, identifying the charge-sensitive beta5-alpha1 loop of the catalytic domain as the electrostatic Bcl-2 binding determinant.\",\n      \"evidence\": \"Heteronuclear NMR, peptide library assay, site-directed mutagenesis\",\n      \"pmids\": [\"22523079\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of the full FKBP8-Bcl-2 complex not solved\", \"Relationship of this interface to PPIase catalysis not addressed\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified a Ca2+/S100-dependent brake on the HCV complex, showing S100 proteins bind FKBP8 and disrupt both Hsp90 and NS5A interactions to suppress viral replication.\",\n      \"evidence\": \"GST/S-tag pulldown, SPR, HCV replicon replication assay\",\n      \"pmids\": [\"23522085\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological S100 levels needed for regulation unknown\", \"Overlap with CaM regulation of the same surface not dissected\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Recast FKBP8 as a Parkin-independent mitophagy receptor with an N-terminal LIR that preferentially recruits LC3A and a unique ability to escape degradation by translocating to the ER, and defined the TPR-Hsp90 MEEVD carboxylate-clamp interface structurally.\",\n      \"evidence\": \"Y2H, in vitro/in vivo pulldowns, LIR mutants, mitophagy flux assays; X-ray crystallography with MEEVD peptide and mutagenesis\",\n      \"pmids\": [\"28381481\", \"28278223\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Trigger and machinery for ER translocation not defined\", \"Physiological mitophagy contribution debated across cell types\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrated an ER-stress protective role in heart, showing cardiac FKBP8 loss causes protein aggregation and caspase-12-dependent apoptosis, while finding no mitophagy role in this context.\",\n      \"evidence\": \"Cardiac-specific knockout mice with TAC, IP, ER stress markers, caspase-12 inhibitor rescue (negative for mitophagy)\",\n      \"pmids\": [\"29129702\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cell-type basis for absent mitophagy not explained\", \"Direct misfolded clients in cardiomyocytes not identified\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified regulated FKBP8 turnover as a control node for mTOR and innate immunity, with signal peptide peptidase mediating its intramembrane proteolysis and FKBP8 negatively regulating RLR-VISA antiviral signaling.\",\n      \"evidence\": \"SILAC proteomics, Co-IP, CHX chase, proteasome inhibitors, xenograft; Y2H, reporter and ubiquitination assays\",\n      \"pmids\": [\"30348988\", \"30267576\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological stimuli driving SPP cleavage unknown\", \"Direct vs indirect effects on RLR components not fully separated\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Distinguished a second N-terminal motif, the LIRL, as the OPA1-binding element driving Drp1-independent mitochondrial fragmentation under iron-depletion and hypoxic stress, separating fission from canonical LIR-mediated mitophagy.\",\n      \"evidence\": \"Functional screening, knockout MEF epistasis (Drp1, FIP200, BNIP3/NIX, OPA1), domain mutants, Co-IP with OPA1\",\n      \"pmids\": [\"31908024\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which FKBP8-OPA1 binding promotes fission unclear\", \"How LIR and LIRL functions are coordinated unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Connected FKBP8 to lipid metabolism and uncovered upstream localization control, with FKBP8 suppressing the mTOR/P70S6K/SREBP lipogenic axis and PHB1 governing its mitochondrial pool and mTOR association.\",\n      \"evidence\": \"Overexpression/knockdown with pathway readouts and HFD model; IP-MS, Co-IP and fractionation with PHB1 knockdown\",\n      \"pmids\": [\"34900535\", \"33259040\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct mechanism of lipid reduction beyond mTOR not defined\", \"How PHB1 controls FKBP8 distribution mechanistically unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Diversified FKBP8 functions into autophagy initiation, epithelial barrier control and epigenetic regulation of Bcl-2 stability, including a PPIase-dependent MLCK1 interaction targetable by tacrolimus.\",\n      \"evidence\": \"VPS34 activity and autophagy flux assays with TM-domain mutants; in vitro binding, KO/dominant-negative cells, organoids, mouse and patient biopsies; demethylation and stability assays for KDM1A\",\n      \"pmids\": [\"35090967\", \"35537812\", \"35970393\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How the same protein selects between LIR-driven mitophagy and TM-driven VPS34 autophagy unresolved\", \"In vivo relevance of KDM1A-FKBP8 axis limited to cancer models\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established FKBP8 as the OMM tether for PDZD8 at ER-mitochondria contact sites, providing structural evidence that FKBP8 shapes contact-site architecture and mitochondrial morphology.\",\n      \"evidence\": \"BioID proximity proteomics, CRISPR endogenous tagging, cryo-electron tomography, CLEM and knockout epistasis\",\n      \"pmids\": [\"40246839\", \"38895210\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional output of PDZD8-FKBP8 tethering beyond morphology not fully defined\", \"How tethering integrates with apoptotic and autophagic roles unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Linked FKBP8 contact-site tethering to lipid transport and turnover control, recruiting BLTP1 for mitochondrial lipid export and being degraded by RNF25/circSATB1 to relieve mTOR inhibition.\",\n      \"evidence\": \"Proximity proteomics, Co-IP, lipidomics, ROS and epistasis assays (preprint); Co-IP, ubiquitination and proteasome-inhibitor assays for RNF25\",\n      \"pmids\": [\"39921520\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"BLTP1 lipid-export finding is a preprint awaiting peer review\", \"Directionality and selectivity of lipid transfer not fully established\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Showed FKBP8 acts as an antiviral restriction factor against influenza A, using its TPR domain to bind M2 LIR and recruiting RAB7A/LAMP1 to drive lysosomal degradation of M2.\",\n      \"evidence\": \"AP-MS, Co-IP, overexpression/knockdown/knockout, lysosomal inhibitors, CHX chase and viral replication assays\",\n      \"pmids\": [\"42212595\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Contrast with FKBP8's pro-viral HCV role not mechanistically reconciled\", \"Single-lab finding without independent replication\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How FKBP8 selects among its many mutually exclusive functions—pro- vs anti-apoptotic, mitophagy vs fission vs contact-site tethering, mTOR inhibition vs chaperone activity—through domain occupancy, localization and post-translational control remains the central open question.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking domain state to functional output\", \"In vivo physiological hierarchy of competing roles undetermined\", \"Structural basis of the apoptotic switch in a cellular context unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016853\", \"supporting_discovery_ids\": [3, 15, 26]},\n      {\"term_id\": \"GO:0044183\", \"supporting_discovery_ids\": [26, 13, 11]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [10, 25, 0]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [31, 42, 12]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [26]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005741\", \"supporting_discovery_ids\": [0, 12, 31]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0, 36, 42]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [21, 26, 33]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [0, 3, 24]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [31, 40, 36]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [10, 25, 2]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [26, 12, 11]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [2, 18]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [7, 45, 35]}\n    ],\n    \"complexes\": [\n      \"FKBP8-CaM/Ca2+ complex\",\n      \"Hsp90-FKBP8-NS5A ternary complex\",\n      \"FKBP8-PDZD8 ER-mitochondria tether\",\n      \"26S proteasome (membrane-anchored)\"\n    ],\n    \"partners\": [\n      \"BCL2\",\n      \"HSP90\",\n      \"MTOR\",\n      \"PDZD8\",\n      \"OPA1\",\n      \"PHD2\",\n      \"CALM1\",\n      \"MAP1LC3A\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}