{"gene":"PPIA","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":2011,"finding":"CypA (PPIA) induces leukocyte chemotaxis through direct binding to the ectodomain of CD147 (CD147ECT), independent of its PPIase activity. NMR mapping showed the CD147ECT binding site on CypA overlaps with the PPIase active site, but the PPIase-inactive mutant CyPA(R55A) retains full CD147 binding and chemotaxis activity. Three key residues (H70A, T107A, R69A) in CypA reduce CD147 binding and chemotaxis without affecting PPIase activity.","method":"NMR spectroscopy, site-directed mutagenesis, chemotaxis assay, binding assays with PPIase-inactive mutant","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR structural mapping combined with mutagenesis and functional chemotaxis assays in single study with orthogonal methods","pmids":["21245143"],"is_preprint":false},{"year":2014,"finding":"AIF amino acid residues 370–394 mediate formation of the AIF/CypA protein complex. A synthetic AIF(370–394) peptide inhibits AIF/CypA complex formation in vitro by binding CypA with a KD of 12 μM, and this inhibition prevents mitochondrial AIF release to the nucleus and glutamate-induced cell death in HT-22 neurons, equivalent to CypA-siRNA knockdown.","method":"In vitro binding assay (KD measurement), peptide inhibition of complex formation, mitochondrial membrane potential assay, CypA-siRNA knockdown, cell death assay","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal inhibition with defined KD, siRNA comparison, multiple functional readouts in single study","pmids":["24434516"],"is_preprint":false},{"year":2017,"finding":"NMR spectroscopy and biochemical studies mapped the binding site of AIF(Δ1–121) and the AIF(370–394) peptide on CypA to a surface region very close to the CypA catalytic pocket, partially overlapping with the cyclosporin A binding site. A molecular model of the complex was proposed, showing the central region V374–K384 of AIF peptide interacts with the F46–G75 region of CypA.","method":"NMR spectroscopy, molecular modeling/docking, biochemical binding studies","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR structural mapping with biochemical validation and molecular modeling, multiple orthogonal methods","pmids":["28442737"],"is_preprint":false},{"year":2018,"finding":"CypA inhibits AIP4-mediated K48-linked ubiquitination of influenza A virus matrix protein M1 at K102 and K104 by impairing the interaction between AIP4 and M1, thereby preventing ubiquitin-proteasome-mediated M1 degradation and regulating nuclear export of M1. Recombinant IAV with M1(K102R/K104R) mutations could not be rescued, demonstrating these ubiquitination sites are essential for IAV replication.","method":"Co-immunoprecipitation, ubiquitination assays, site-directed mutagenesis, virus rescue assay, Western blot","journal":"Virologica Sinica","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, mutagenesis with functional virus rescue, multiple orthogonal methods in single study","pmids":["30328013"],"is_preprint":false},{"year":2024,"finding":"PPIA physically binds to NRF2 via its trans-proline 174-harboring hydrophobic interdomain linker sequence, blocking ubiquitin/KEAP1-mediated NRF2 degradation. X-ray co-crystal structure confirmed the direct PPIA–NRF2 interaction; ablation of PPIA promotes NRF2 ubiquitination and degradation. Cyclosporin A (CsA) impairs NRF2–PPIA interaction, inducing NRF2 degradation.","method":"X-ray co-crystallography, co-immunoprecipitation, ubiquitination assay, PPIA knockout/ablation, CsA treatment","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — X-ray co-crystal structure plus biochemical validation (Co-IP, ubiquitination assays, KO), multiple orthogonal methods","pmids":["38830868"],"is_preprint":false},{"year":2008,"finding":"Knockdown of CypA (PPIA) by RNAi in U2OS cells disrupts F-actin structure and decreases anchorage-independent growth, proliferation, and migration. CypA was found to bind N-WASP by in vitro and in vivo binding assays, and loss of CypA enhances N-WASP degradation, suggesting CypA stabilizes N-WASP to support N-WASP/Arp2/3-mediated F-actin polymerization. CsA treatment phenocopies CypA knockdown, implicating PPIase activity.","method":"RNAi knockdown, in vitro and in vivo binding assays (N-WASP), pulse-chase degradation assay, CsA treatment, F-actin imaging","journal":"Molecular and cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single Co-IP/pulldown plus RNAi phenotype, CsA confirmation; single lab","pmids":["18704644"],"is_preprint":false},{"year":2010,"finding":"CypA-induced monocyte migration, MMP-9 expression, IL-6 and TNF-alpha release, and ERK1/2-mediated NF-κB activation are significantly inhibited when EMMPRIN (CD147) is blocked on monocytes, identifying CypA–EMMPRIN interaction as a key pro-inflammatory signaling pathway.","method":"Chemotaxis assay, ELISA, Western blot (ERK1/2-NF-κB), EMMPRIN blocking antibody","journal":"Atherosclerosis","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — receptor blocking plus multiple downstream readouts; single lab","pmids":["21035802"],"is_preprint":false},{"year":2012,"finding":"CypA facilitates translocation of anthrax lethal factor fusion protein LF(N)DTA across endosomal membranes into the cytosol. In vitro, CypA bound directly to LF(N)DTA and DTA but not to LF. An antibody against CypA blocked release of LF(N)DTA from endosomal vesicles in vitro. Cyclosporin A (inhibiting CypA PPIase activity) prevented cytosolic delivery and protected cells from intoxication.","method":"In vitro binding assay (pulldown), anti-CypA antibody blocking, endosomal vesicle release assay, CsA inhibition, cell intoxication assay","journal":"Cellular microbiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding assay plus functional blocking antibody and pharmacological inhibition with orthogonal readouts","pmids":["20946244"],"is_preprint":false},{"year":2012,"finding":"CypA directly binds to IRF9 (the DNA-binding component of ISGF3) via its PPIase pocket; Cyp inhibitors (CsA, alisporivir, SCY-635) prevent IRF9–CypA complex formation. CypA binds specifically to the C-terminal IRF-association domain (IAD) of IRF9 but not to the DNA-binding or linker domains. HCV NS5A competes with IRF9 for CypA binding, preventing IRF9–CypA complex formation.","method":"Cellular and recombinant pulldown assays, domain mapping, competitive binding with NS5A","journal":"Journal of hepatology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — reciprocal pulldowns with domain mapping and competitive inhibitor, single lab","pmids":["22902549"],"is_preprint":false},{"year":2014,"finding":"GST pulldown and co-immunoprecipitation showed CypA interacts with NF-κB subunit p65/RelA. A CypA-binding consensus-like sequence was identified within p65 at N-terminal residues 170–176. CypA stabilized p65 protein and promoted its nuclear translocation, resulting in enhanced NF-κB transcriptional activity. NOTE: This paper has been RETRACTED.","method":"GST pulldown, co-immunoprecipitation, truncation and site-directed mutagenesis, luciferase assay, EMSA, immunofluorescence","journal":"PloS one","confidence":"Low","confidence_rationale":"Tier 3 / Weak — paper is retracted; findings cannot be relied upon","pmids":["25119989"],"is_preprint":false},{"year":2015,"finding":"PPIA knockout mice have significantly less fat mass and smaller adipocytes than wild-type. PPIA silencing in 3T3L1 cells impairs adipocyte differentiation with reduced PPARG, C/EBPA, and C/EBPB expression at late differentiation stages; PPIA-KO MEFs show the same phenotype, rescued by PPIA re-expression. This identifies PPIA as a novel adipogenic factor.","method":"PPIA knockout mice, siRNA knockdown, gene overexpression/rescue, adipocyte differentiation assay, gene expression analysis","journal":"Obesity (Silver Spring, Md.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse phenotype corroborated by in vitro KD and rescue, multiple models","pmids":["26347493"],"is_preprint":false},{"year":2000,"finding":"Targeted disruption of both copies of mouse Ppia in embryonic stem (ES) cells demonstrated that CypA is not essential for mammalian cell viability or hematopoietic differentiation in vitro. The Ppia gene was characterized as consisting of 5 exons and 4 introns (~4.5 kb), mapping to chromosome 11. A 369-bp proximal promoter region containing TATA box and Sp1, AP-2, GATA, c-Myb, NF-IL-6 sites was sufficient for high-level reporter expression.","method":"Gene targeting (homologous recombination), ES cell knockout, reporter gene assay, hematopoietic differentiation","journal":"Genomics","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout with functional validation; cell viability and differentiation assays, clear negative result","pmids":["10964515"],"is_preprint":false},{"year":2016,"finding":"Ppia−/− mice show low bone mineral density, reduced osteoblast numbers, and increased osteoclast numbers. Ppia−/− osteoblasts have decreased osteogenic differentiation; in osteoblasts, CypA is necessary for BMP-2-induced Smad phosphorylation. In osteoclasts, loss of CypA activates BtK and subsequently integrates with TRAF6 and/or c-fos signaling to induce NFATc1, increasing osteoclastic activity.","method":"Ppia−/− mouse model, osteoblast and osteoclast isolation and differentiation assay, BMP-2 signaling (Smad phosphorylation), overexpression and gene silencing, Western blot","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse model with cell-specific pathway dissection, single lab","pmids":["26932182"],"is_preprint":false},{"year":2019,"finding":"STAT3 transcriptionally activates CypA expression by binding to a STAT3-responsive element (SRE) in the CypA promoter, as confirmed by ChIP and luciferase assays. STAT3-induced CypA expression mediates apoptosis of human umbilical vein endothelial cells in vitro.","method":"ChIP assay, luciferase reporter assay, RT-qPCR, immunostaining, cell viability and apoptosis assays","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus luciferase confirming STAT3-dependent transcription of CypA, functional apoptosis readout","pmids":["31494257"],"is_preprint":false},{"year":2014,"finding":"HIF-1α directly binds to the hypoxia response element (HRE) in the CypA promoter and regulates CypA expression in pancreatic ductal adenocarcinoma cells, as shown by chromatin immunoprecipitation. Suppression or overexpression of HIF-1α correspondingly decreases or increases CypA mRNA and protein.","method":"Chromatin immunoprecipitation (ChIP), HIF-1α overexpression/knockdown, RT-PCR, Western blot","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP assay with gain/loss-of-function validation; single lab","pmids":["24662981"],"is_preprint":false},{"year":2021,"finding":"Cryo-electron tomography and subtomogram averaging of native HIV-1 capsids revealed two distinct IP6 binding sites (at R18 and K25) and the structural modes of cyclophilin A interaction with HIV-1 capsomers. An all-atom model of the complete HIV-1 capsid was constructed.","method":"Cryo-electron tomography, subtomogram averaging, all-atom molecular modeling, free energy calculations","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 1 / Moderate — cryo-ET structural determination with free energy calculations and all-atom model; rigorous structural approach","pmids":["34797722"],"is_preprint":false},{"year":2018,"finding":"CypA directly interacts with influenza A virus matrix protein M1; this interaction was confirmed by pulldown and co-immunoprecipitation in vitro and in vivo. CypA restricts IAV replication by promoting ubiquitin-proteasome-mediated M1 degradation.","method":"Co-immunoprecipitation, pulldown, Western blot, viral replication assay","journal":"Proteomics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP/pulldown; interaction first described here for M1 with limited mechanistic follow-up in this paper (deeper mechanism in PMID 30328013)","pmids":["30281201"],"is_preprint":false},{"year":2022,"finding":"CypA interacts with SERPINH1 (identified by LC-MS/MS as a CypA-binding protein) in trophoblast cells. CypA promotes extracellular matrix (collagen I, fibronectin) production and inhibits epithelial-mesenchymal transition through the TGF-β/Smad3 signaling pathway. Silencing SERPINH1 reversed these CypA-induced effects.","method":"LC-MS/MS protein interaction discovery, stable OE/KD cell models, RNA-seq, Western blot, immunohistochemistry","journal":"Molecular and cellular endocrinology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — MS-identified binding partner with siRNA functional validation and pathway analysis, single lab","pmids":["35304192"],"is_preprint":false},{"year":2025,"finding":"PARP3 directly interacts with Ppia and catalyzes mono ADP-ribosylation of Ppia at Glu140. Mutation of E140 inhibited inflammatory response, mono ADP-ribosylation, and secretion of Ppia. Ppia mediates PARP3-promoted macrophage inflammation via NF-κB signaling. PARP3 inhibitor ME0328 reduced NF-κB activation and inflammatory cytokines in ALI.","method":"Immunoprecipitation, site-directed mutagenesis (E140), RNA-seq, ELISA, Western blot, in vivo ALI model","journal":"Molecular medicine (Cambridge, Mass.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP confirming interaction, mutagenesis identifying modification site, functional KD and in vivo validation; single lab","pmids":["40461998"],"is_preprint":false},{"year":2025,"finding":"CypA stabilizes the ferroptosis suppressor SLC7A11 by competitively binding to its K37 site, blocking TRIM3-mediated ubiquitination and proteasomal degradation of SLC7A11. This interaction maintains cystine uptake and glutathione biosynthesis, attenuating ferroptosis induced by cisplatin/paclitaxel in NSCLC. CypA knockout or CsA treatment restores ferroptosis and reverses drug resistance.","method":"Co-immunoprecipitation, site-directed mutagenesis (K37), ubiquitination assay, CypA KO, CsA inhibition, in vitro and in vivo chemosensitivity assays","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with mutagenesis identifying binding site, KO and pharmacological inhibition with functional readouts; single lab","pmids":["41203575"],"is_preprint":false},{"year":2025,"finding":"The ALS-associated K76E mutation in PPIA significantly reduces its cis-trans isomerase enzyme activity without altering structure, monodispersity, or substrate recognition. Relaxation dispersion NMR revealed K76E disrupts key protein dynamics and an allosteric network essential for isomerase activity; the conformational exchange process is ~10-fold slower in K76E than wild-type, explaining reduced activity.","method":"Relaxation dispersion NMR, biochemical enzyme activity assay, biophysical characterization (structure, monodispersity), theoretical kinetic analysis","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR dynamics plus enzyme activity assay with mutagenesis; mechanistically rigorous single study","pmids":["40587259"],"is_preprint":false},{"year":2023,"finding":"CypA is recruited to orthopoxvirus factories and virions through interaction with the viral capsid protein L3, antagonizing TRIM5α-mediated antiviral restriction. This interaction is prevented by CsA and non-immunosuppressive CsA derivatives (alisporivir, NIM811). Both the proviral effect of CypA and the antiviral effect of CsA are dependent on TRIM5α.","method":"Cyclosporine A and derivative treatment, TRIM5α-dependent rescue assays, antiviral assays","journal":"Nature","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological and genetic epistasis in Nature publication; single lab but high-quality methods","pmids":["37558876"],"is_preprint":false},{"year":2024,"finding":"CypA directly interacts with TAF15, stabilizing it by suppressing proteasome-mediated degradation and promoting its nuclear entry. TAF15 in turn positively regulates STAT5A, which promotes CypA expression while miR-514a-3p directly binds the 3'-UTR of CypA to suppress its expression, forming a CypA/TAF15/STAT5A/miR-514a-3p feedback loop driving EMT and ovarian cancer metastasis.","method":"Co-immunoprecipitation, mass spectrometry, proteasome inhibition assay, 3'-UTR reporter, in vivo xenograft","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP/MS identification of TAF15, proteasomal stabilization assay, functional in vivo confirmation; single lab","pmids":["39402372"],"is_preprint":false},{"year":2023,"finding":"CypA colocalizes with pseudouridine synthase dyskerin in the nucleolus and directly interacts with dyskerin, which is the catalytic component of H/ACA RNPs. Dyskerin prolines (mutated in X-linked dyskeratosis congenita) are implicated as CypA client residues, suggesting CypA acts as a chaperone modulating dyskerin activity and RNP assembly.","method":"Colocalization imaging (immunofluorescence), direct interaction assay, structural analysis of proline mutations","journal":"Genes","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single colocalization and interaction assay; mechanistic follow-up limited; single lab","pmids":["37761906"],"is_preprint":false},{"year":2024,"finding":"CRISPR-KO and endogenous point-mutant (CypA unable to bind HIV-1 CA) cell lines demonstrated that cyclosporine A effects on HIV-1 infection are the direct result of blocking CA–CypA interactions, independent of CypA interactions with MX2 or other cellular proteins. Abrogation of CypA-CA interaction combined with loss of MX2 GTPase activity conferred enhanced MX2 antiviral activity and altered nucleoporin requirements.","method":"CRISPR-Cas9/AAV endogenous point mutation, CypA knockout, CsA treatment, HIV-1 infection assay, epistasis with MX2 GTPase mutants","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 2 / Strong — CRISPR endogenous mutagenesis with multiple CA and CypA variants providing clean genetic epistasis; rigorous controls","pmids":["38512975"],"is_preprint":false},{"year":2024,"finding":"circ_005077 interacts with CypA and inhibits its ubiquitin-proteasome-mediated degradation, thereby promoting the interaction between CypA and p47phox to enhance NADPH oxidase activity and ROS generation, inducing ferroptosis in cardiomyocytes under lipotoxic conditions.","method":"RNA-protein interaction assay, Co-immunoprecipitation, ubiquitination assay, NADPH oxidase activity measurement, ferroptosis markers","journal":"Cardiovascular diabetology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — interaction demonstrated by Co-IP but primary focus is on the circRNA; mechanistic CypA findings are secondary; single lab","pmids":["38622592"],"is_preprint":false},{"year":2024,"finding":"CypA/MMP9 signaling pathway mediates ROS-induced blood-brain barrier disruption and delirium-like behavior in aged mice following anesthesia/surgery. ROS scavenging prevented CypA/MMP9 upregulation and BBB permeability increase; CypA inhibitor (CsA) abolished MMP9 elevation and reversed BBB damage, establishing CypA as upstream of MMP9 in this pathway.","method":"Western blot, CsA pharmacological inhibition, ROS scavenger (NAC), IgG permeability assay, behavioral tests","journal":"Frontiers in aging neuroscience","confidence":"Low","confidence_rationale":"Tier 3 / Weak — pharmacological inhibition only (no direct binding/mutagenesis); pathway position inferred from CsA and NAC treatment","pmids":["36337710"],"is_preprint":false}],"current_model":"PPIA (CypA) is a peptidyl-prolyl cis-trans isomerase whose PPIase activity (dependent on catalytic pocket dynamics, disrupted by the ALS-associated K76E allosteric mutation) mediates protein folding and stabilization of multiple client proteins including NRF2 (blocking KEAP1/ubiquitin-mediated degradation via direct binding to a proline 174-containing linker), SLC7A11 (blocking TRIM3-mediated ubiquitination at K37), N-WASP, and TAF15; extracellular CypA acts as a cytokine/chemokine by binding directly to the ectodomain of CD147/EMMPRIN independent of PPIase activity to drive NF-κB/MAPK-mediated inflammation, leukocyte chemotaxis, and cancer stem cell signaling; intracellularly, CypA forms a pro-apoptotic complex with AIF (via AIF residues 370–394 near the PPIase pocket) that translocates to the nucleus to cause DNA degradation, and is also mono-ADP-ribosylated at Glu140 by PARP3 to promote NF-κB-dependent macrophage inflammation; in the context of HIV-1 and other viruses, CypA directly engages the viral capsid to modulate uncoating and TRIM5α-dependent restriction; and in bone biology, CypA supports osteoblast differentiation via BMP-2/Smad signaling while restraining osteoclastogenesis through the BtK/TRAF6/NFATc1 axis."},"narrative":{"mechanistic_narrative":"PPIA (cyclophilin A, CypA) is a peptidyl-prolyl cis-trans isomerase whose catalytic activity depends on a defined dynamic allosteric network within its active-site pocket, as shown by the ALS-associated K76E mutation that selectively slows conformational exchange and impairs isomerase activity without altering overall structure [PMID:40587259]. A dominant theme of its biology is the stabilization of client proteins against ubiquitin-mediated degradation: CypA directly binds the proline-174 interdomain linker of NRF2 to block KEAP1/ubiquitin-driven turnover (confirmed by co-crystal structure) [PMID:38830868], competitively occupies the K37 ubiquitination site of SLC7A11 to prevent TRIM3-mediated degradation and restrain ferroptosis [PMID:41203575], and stabilizes N-WASP [PMID:18704644] and TAF15 [PMID:39402372] to support actin-based motility and cancer cell EMT respectively. A second, PPIase-independent role is that of an extracellular pro-inflammatory mediator: CypA binds the ectodomain of CD147/EMMPRIN—via a surface overlapping but distinct from the PPIase pocket—to drive leukocyte chemotaxis and ERK1/2–NF-κB signaling [PMID:21245143, PMID:21035802]. Intracellularly, CypA forms a pro-apoptotic complex with AIF through AIF residues 370–394 binding near the CypA catalytic pocket, mediating mitochondrial AIF release and cell death [PMID:24434516, PMID:28442737]. CypA is itself transcriptionally controlled by STAT3, HIF-1α, and TAF15/STAT5A inputs [PMID:31494257, PMID:24662981, PMID:39402372] and is post-translationally mono-ADP-ribosylated at Glu140 by PARP3 to promote NF-κB-dependent macrophage inflammation [PMID:40461998]. In viral infection, CypA directly engages viral capsids to modulate restriction and replication—binding the HIV-1 capsid to govern cyclosporine-sensitive infection and MX2/TRIM5α outcomes [PMID:34797722, PMID:38512975], the orthopoxvirus L3 protein to antagonize TRIM5α [PMID:37558876], and influenza M1 to regulate its ubiquitination and nuclear export [PMID:30328013]. CypA is dispensable for cell viability and hematopoietic differentiation [PMID:10964515] but supports adipogenesis and bone homeostasis, promoting osteoblast differentiation via BMP-2/Smad while restraining osteoclastogenesis through a BtK/TRAF6/NFATc1 axis [PMID:26347493, PMID:26932182].","teleology":[{"year":2000,"claim":"Established whether CypA is essential, defining the baseline for all subsequent functional studies by showing it is dispensable for viability.","evidence":"Homozygous Ppia disruption in mouse ES cells with viability and hematopoietic differentiation assays","pmids":["10964515"],"confidence":"High","gaps":["Negative result in vitro does not address tissue-specific or stress-dependent functions","Does not test redundancy with other cyclophilins"]},{"year":2010,"claim":"Defined the extracellular pro-inflammatory axis by showing CypA signals through EMMPRIN/CD147 to drive monocyte migration and NF-κB activation.","evidence":"Chemotaxis, ELISA, ERK1/2-NF-κB Western blot with EMMPRIN blocking antibody on monocytes","pmids":["21035802"],"confidence":"Medium","gaps":["Receptor-blocking antibody does not map the molecular interface","Does not resolve PPIase dependence"]},{"year":2011,"claim":"Resolved whether CypA's chemotactic function requires its enzymatic activity, showing CD147 binding and chemotaxis are PPIase-independent and mediated by a distinct surface.","evidence":"NMR mapping, site-directed mutagenesis, and chemotaxis with the PPIase-inactive R55A mutant","pmids":["21245143"],"confidence":"High","gaps":["Does not establish in vivo relevance of identified residues","Structure of the full CypA–CD147 ectodomain complex not solved"]},{"year":2014,"claim":"Mapped the pro-apoptotic CypA–AIF complex and showed its disruption blocks neuronal death, defining a druggable interface for AIF-dependent apoptosis.","evidence":"In vitro binding (KD 12 μM), peptide inhibition, AIF translocation and cell death assays in HT-22 neurons with siRNA comparison","pmids":["24434516"],"confidence":"High","gaps":["Whether PPIase catalysis acts on AIF not resolved","In vivo neuroprotection not tested"]},{"year":2017,"claim":"Localized the AIF binding site to a surface near the CypA catalytic pocket overlapping the cyclosporin A site, structurally rationalizing the complex.","evidence":"NMR spectroscopy, biochemical binding, and molecular docking of AIF peptide onto CypA","pmids":["28442737"],"confidence":"High","gaps":["Model not validated by co-crystal structure","Functional consequence of catalytic-pocket proximity untested"]},{"year":2014,"claim":"Identified transcriptional control of CypA by HIF-1α via a promoter HRE, linking CypA expression to hypoxic tumor signaling.","evidence":"ChIP with HIF-1α gain/loss-of-function and RT-PCR/Western in pancreatic adenocarcinoma cells","pmids":["24662981"],"confidence":"Medium","gaps":["Single tumor context","Downstream functional output of induced CypA not dissected here"]},{"year":2008,"claim":"Connected CypA to cytoskeletal dynamics by showing it stabilizes N-WASP to support F-actin polymerization, proliferation, and migration.","evidence":"RNAi, in vitro/in vivo N-WASP binding, pulse-chase degradation, CsA treatment, F-actin imaging in U2OS cells","pmids":["18704644"],"confidence":"Medium","gaps":["Single lab and single Co-IP","Direct enzymatic action on N-WASP not demonstrated"]},{"year":2015,"claim":"Demonstrated a metabolic role by identifying CypA as an adipogenic factor required for adipocyte differentiation.","evidence":"Ppia knockout mice, 3T3L1 siRNA, KO MEF rescue, and adipogenic gene expression","pmids":["26347493"],"confidence":"Medium","gaps":["Molecular client mediating adipogenesis unidentified","PPIase dependence not tested"]},{"year":2016,"claim":"Established opposing roles of CypA in bone, promoting osteoblast BMP-2/Smad signaling while restraining osteoclastogenesis via BtK/TRAF6/NFATc1.","evidence":"Ppia−/− mice with cell-specific osteoblast/osteoclast differentiation and signaling assays","pmids":["26932182"],"confidence":"Medium","gaps":["Direct molecular targets in each cell type not defined","Single lab"]},{"year":2019,"claim":"Showed STAT3 directly transactivates CypA, with induced CypA mediating endothelial apoptosis.","evidence":"ChIP, luciferase, RT-qPCR and apoptosis assays in HUVECs","pmids":["31494257"],"confidence":"Medium","gaps":["Apoptotic effector mechanism downstream of CypA not defined"]},{"year":2012,"claim":"Extended CypA's role to pathogen entry and antiviral signaling, showing it binds anthrax LF(N)DTA to enable cytosolic translocation and binds IRF9's IAD to support interferon signaling.","evidence":"In vitro binding, anti-CypA blocking, endosomal release and intoxication assays; domain-mapped pulldowns with NS5A competition","pmids":["20946244","22902549"],"confidence":"Medium","gaps":["Physiological significance of IRF9 interaction not established in vivo","Catalytic versus scaffolding role unresolved"]},{"year":2018,"claim":"Defined a mechanistic role for CypA in restricting influenza by modulating AIP4-dependent ubiquitination of viral M1 at K102/K104, controlling M1 nuclear export.","evidence":"Co-IP, ubiquitination assays, mutagenesis, and virus rescue","pmids":["30328013","30281201"],"confidence":"High","gaps":["Whether CypA acts catalytically on M1 not shown","In vivo antiviral relevance untested"]},{"year":2021,"claim":"Provided structural detail of CypA engagement with the native HIV-1 capsid lattice within an all-atom capsid model.","evidence":"Cryo-electron tomography, subtomogram averaging and free energy calculations","pmids":["34797722"],"confidence":"High","gaps":["Does not resolve functional outcome of binding in cells"]},{"year":2023,"claim":"Established CypA capsid binding as the key determinant of cyclosporine-sensitive viral restriction across viruses, antagonizing TRIM5α for orthopoxvirus and HIV-1.","evidence":"CsA/derivative treatment with TRIM5α-dependent rescue (poxvirus L3) and CRISPR endogenous CypA/CA point-mutant epistasis with MX2 (HIV-1)","pmids":["37558876","38512975"],"confidence":"High","gaps":["Whether PPIase catalysis on capsid is required not fully resolved","Mechanism of TRIM5α antagonism at molecular level incomplete"]},{"year":2024,"claim":"Defined the structural basis of CypA-dependent NRF2 stabilization, showing direct binding to a proline-174 linker blocks KEAP1/ubiquitin-mediated degradation.","evidence":"X-ray co-crystallography, Co-IP, ubiquitination assay, PPIA ablation and CsA treatment","pmids":["38830868"],"confidence":"High","gaps":["Whether cis-trans isomerization of P174 is the mechanism not directly proven","In vivo NRF2 pathway consequences not fully mapped"]},{"year":2024,"claim":"Identified a CypA-stabilized TAF15 feedback loop driving ovarian cancer EMT and metastasis.","evidence":"Co-IP/MS, proteasome inhibition, 3'-UTR reporter and xenograft assays","pmids":["39402372"],"confidence":"Medium","gaps":["Single lab","Direct enzymatic basis of TAF15 stabilization not shown"]},{"year":2025,"claim":"Showed CypA blocks ferroptosis by competitively shielding SLC7A11 K37 from TRIM3-mediated ubiquitination, linking CypA to chemoresistance.","evidence":"Co-IP, K37 mutagenesis, ubiquitination assay, CypA KO/CsA and in vivo chemosensitivity in NSCLC","pmids":["41203575"],"confidence":"Medium","gaps":["Single lab","Catalytic versus competitive-binding contribution not separated"]},{"year":2025,"claim":"Defined PARP3-catalyzed mono-ADP-ribosylation of CypA at Glu140 as a switch enabling NF-κB-dependent macrophage inflammation and CypA secretion.","evidence":"Co-IP, E140 mutagenesis, RNA-seq, ELISA and in vivo acute lung injury model with PARP3 inhibitor","pmids":["40461998"],"confidence":"Medium","gaps":["Single lab","How E140 modification alters CypA secretion mechanistically unresolved"]},{"year":2025,"claim":"Demonstrated that the ALS-associated K76E mutation impairs CypA isomerase activity by disrupting a dynamic allosteric network rather than the fold, mechanistically linking enzyme dynamics to disease.","evidence":"Relaxation dispersion NMR, enzyme activity assay and biophysical characterization","pmids":["40587259"],"confidence":"High","gaps":["Does not establish which client/folding defect drives ALS pathology","In vivo phenotype of K76E not tested"]},{"year":null,"claim":"It remains unresolved which CypA functions strictly require its cis-trans isomerase catalysis versus scaffolding/competitive binding, and how a single catalytic surface coordinates its many client-stabilization, capsid, and inflammatory roles.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No systematic separation-of-function analysis across clients","Unifying basis for client selectivity unknown","In vivo contribution of individual interactions to disease undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016853","term_label":"isomerase activity","supporting_discovery_ids":[20]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[4,19,5,22]},{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[4,19]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,6]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1,5]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,6,18]},{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[23]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[22]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune 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Exerts a strong chemotactic effect on leukocytes partly through activation of one of its membrane receptors BSG/CD147, initiating a signaling cascade that culminates in MAPK/ERK activation (PubMed:11943775, PubMed:21245143). Activates endothelial cells (ECs) in a pro-inflammatory manner by stimulating activation of NF-kappa-B and ERK, JNK and p38 MAP-kinases and by inducing expression of adhesion molecules including SELE and VCAM1 (PubMed:15130913). Induces apoptosis in ECs by promoting the FOXO1-dependent expression of CCL2 and BCL2L11 which are involved in EC chemotaxis and apoptosis (PubMed:31063815). In response to oxidative stress, initiates proapoptotic and antiapoptotic signaling in ECs via activation of NF-kappa-B and AKT1 and up-regulation of antiapoptotic protein BCL2 (PubMed:23180369). Negatively regulates MAP3K5/ASK1 kinase activity, autophosphorylation and oxidative stress-induced apoptosis mediated by MAP3K5/ASK1 (PubMed:26095851). Necessary for the assembly of TARDBP in heterogeneous nuclear ribonucleoprotein (hnRNP) complexes and regulates TARDBP binding to RNA UG repeats and TARDBP-dependent expression of HDAC6, ATG7 and VCP which are involved in clearance of protein aggregates (PubMed:25678563). Plays an important role in platelet activation and aggregation (By similarity). Regulates calcium mobilization and integrin ITGA2B:ITGB3 bidirectional signaling via increased ROS production as well as by facilitating the interaction between integrin and the cell cytoskeleton (By similarity). Binds heparan sulfate glycosaminoglycans (PubMed:11943775). Inhibits replication of influenza A virus (IAV) (PubMed:19207730). Inhibits ITCH/AIP4-mediated ubiquitination of matrix protein 1 (M1) of IAV by impairing the interaction of ITCH/AIP4 with M1, followed by the suppression of the nuclear export of M1, and finally reduction of the replication of IAV (PubMed:22347431, PubMed:30328013) (Microbial infection) May act as a mediator between human SARS coronavirus nucleoprotein and BSG/CD147 in the process of invasion of host cells by the virus (PubMed:15688292) (Microbial infection) Stimulates RNA-binding ability of HCV NS5A in a peptidyl-prolyl cis-trans isomerase activity-dependent manner (Microbial infection) May act as a receptor for M.genitalium adhesin protein P140 (also called MgPa) (PubMed:29551599, PubMed:33013867)","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/P62937/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/PPIA","classification":"Common Essential","n_dependent_lines":911,"n_total_lines":1090,"dependency_fraction":0.8357798165137614},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"ACTR2","stoichiometry":0.2},{"gene":"CAPZB","stoichiometry":0.2},{"gene":"SAR1B","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/PPIA","total_profiled":1310},"omim":[{"mim_id":"617170","title":"CWC27, SPLICEOSOME-ASSOCIATED CYCLOPHILIN; CWC27","url":"https://www.omim.org/entry/617170"},{"mim_id":"609532","title":"HEPATITIS C VIRUS, SUSCEPTIBILITY TO","url":"https://www.omim.org/entry/609532"},{"mim_id":"608608","title":"PEPTIDYL-PROLYL ISOMERASE A-LIKE PROTEIN 4E; PPIAL4E","url":"https://www.omim.org/entry/608608"},{"mim_id":"606095","title":"PEPTIDYL-PROLYL ISOMERASE H; PPIH","url":"https://www.omim.org/entry/606095"},{"mim_id":"601052","title":"PEPTIDYL-PROLYL CIS/TRANS ISOMERASE, NIMA-INTERACTING, 1; PIN1","url":"https://www.omim.org/entry/601052"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PPIA"},"hgnc":{"alias_symbol":["CYPA"],"prev_symbol":[]},"alphafold":{"accession":"P62937","domains":[{"cath_id":"2.40.100.10","chopping":"4-163","consensus_level":"high","plddt":98.35,"start":4,"end":163}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P62937","model_url":"https://alphafold.ebi.ac.uk/files/AF-P62937-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P62937-F1-predicted_aligned_error_v6.png","plddt_mean":98.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PPIA","jax_strain_url":"https://www.jax.org/strain/search?query=PPIA"},"sequence":{"accession":"P62937","fasta_url":"https://rest.uniprot.org/uniprotkb/P62937.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P62937/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P62937"}},"corpus_meta":[{"pmid":"18389077","id":"PMC_18389077","title":"Evolution of a TRIM5-CypA splice isoform in 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communications","url":"https://pubmed.ncbi.nlm.nih.gov/24613845","citation_count":5,"is_preprint":false},{"pmid":"35369502","id":"PMC_35369502","title":"MxB Disrupts Hepatitis C Virus NS5A-CypA Complex: Insights From a Combined Theoretical and Experimental Approach.","date":"2022","source":"Frontiers in microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/35369502","citation_count":4,"is_preprint":false},{"pmid":"31949770","id":"PMC_31949770","title":"EMMPRIN-CypA contributes to the inflammatory processes in human periodontitis through infiltrating CD68+ inflammatory cells.","date":"2018","source":"International journal of clinical and experimental pathology","url":"https://pubmed.ncbi.nlm.nih.gov/31949770","citation_count":4,"is_preprint":false},{"pmid":"40012358","id":"PMC_40012358","title":"Discovery of Novel Oxazolo[4,3-f]purine Derivatives as Antitumor Agents through PPIA Interaction.","date":"2025","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/40012358","citation_count":4,"is_preprint":false},{"pmid":"33116728","id":"PMC_33116728","title":"Cyclophilin A (CyPA) as a Novel Biomarker for Early Detection of Diabetic Nephropathy in an Animal Model.","date":"2020","source":"Diabetes, metabolic syndrome and obesity : targets and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/33116728","citation_count":4,"is_preprint":false},{"pmid":"41203575","id":"PMC_41203575","title":"CypA Mediates Non-Small Cell Lung Cancer Chemoresistance by Attenuating Ferroptosis via Stabilizing SLC7A11.","date":"2025","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/41203575","citation_count":3,"is_preprint":false},{"pmid":"40461998","id":"PMC_40461998","title":"PARP3 promotes macrophage inflammation via mono ADP ribosylation of Ppia Glu140.","date":"2025","source":"Molecular medicine (Cambridge, 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CCS","url":"https://pubmed.ncbi.nlm.nih.gov/41316398","citation_count":2,"is_preprint":false},{"pmid":"38361405","id":"PMC_38361405","title":"Autophagy inhibitors 3-MA and BAF may attenuate hippocampal neuronal necroptosis after global cerebral ischemia-reperfusion injury in male rats by inhibiting the interaction of the RIP3/AIF/CypA complex.","date":"2024","source":"Journal of neuroscience research","url":"https://pubmed.ncbi.nlm.nih.gov/38361405","citation_count":2,"is_preprint":false},{"pmid":"40587259","id":"PMC_40587259","title":"A Disease-Associated Mutation Impedes PPIA through Allosteric Dynamics Modulation.","date":"2025","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/40587259","citation_count":1,"is_preprint":false},{"pmid":"39684321","id":"PMC_39684321","title":"PPIA-coExp: Discovering Context-Specific Biomarkers Based on Protein-Protein Interactions, Co-Expression Networks, and Expression Data.","date":"2024","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/39684321","citation_count":1,"is_preprint":false},{"pmid":"39279526","id":"PMC_39279526","title":"PPIA, HRPT1, and PGK1 genes as the appropriate combination for RT-qPCR normalization in alveolar and femoral bone remodeling in olanzapine-treated rats.","date":"2024","source":"Acta pharmaceutica (Zagreb, Croatia)","url":"https://pubmed.ncbi.nlm.nih.gov/39279526","citation_count":1,"is_preprint":false},{"pmid":"40594293","id":"PMC_40594293","title":"Multidimensional pan-cancer analysis reveals the impact of PPIA on tumor epigenetic modifications and immune regulation.","date":"2025","source":"Scientific 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NMR mapping showed the CD147ECT binding site on CypA overlaps with the PPIase active site, but the PPIase-inactive mutant CyPA(R55A) retains full CD147 binding and chemotaxis activity. Three key residues (H70A, T107A, R69A) in CypA reduce CD147 binding and chemotaxis without affecting PPIase activity.\",\n      \"method\": \"NMR spectroscopy, site-directed mutagenesis, chemotaxis assay, binding assays with PPIase-inactive mutant\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR structural mapping combined with mutagenesis and functional chemotaxis assays in single study with orthogonal methods\",\n      \"pmids\": [\"21245143\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"AIF amino acid residues 370–394 mediate formation of the AIF/CypA protein complex. A synthetic AIF(370–394) peptide inhibits AIF/CypA complex formation in vitro by binding CypA with a KD of 12 μM, and this inhibition prevents mitochondrial AIF release to the nucleus and glutamate-induced cell death in HT-22 neurons, equivalent to CypA-siRNA knockdown.\",\n      \"method\": \"In vitro binding assay (KD measurement), peptide inhibition of complex formation, mitochondrial membrane potential assay, CypA-siRNA knockdown, cell death assay\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal inhibition with defined KD, siRNA comparison, multiple functional readouts in single study\",\n      \"pmids\": [\"24434516\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"NMR spectroscopy and biochemical studies mapped the binding site of AIF(Δ1–121) and the AIF(370–394) peptide on CypA to a surface region very close to the CypA catalytic pocket, partially overlapping with the cyclosporin A binding site. A molecular model of the complex was proposed, showing the central region V374–K384 of AIF peptide interacts with the F46–G75 region of CypA.\",\n      \"method\": \"NMR spectroscopy, molecular modeling/docking, biochemical binding studies\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR structural mapping with biochemical validation and molecular modeling, multiple orthogonal methods\",\n      \"pmids\": [\"28442737\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CypA inhibits AIP4-mediated K48-linked ubiquitination of influenza A virus matrix protein M1 at K102 and K104 by impairing the interaction between AIP4 and M1, thereby preventing ubiquitin-proteasome-mediated M1 degradation and regulating nuclear export of M1. Recombinant IAV with M1(K102R/K104R) mutations could not be rescued, demonstrating these ubiquitination sites are essential for IAV replication.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, site-directed mutagenesis, virus rescue assay, Western blot\",\n      \"journal\": \"Virologica Sinica\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, mutagenesis with functional virus rescue, multiple orthogonal methods in single study\",\n      \"pmids\": [\"30328013\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PPIA physically binds to NRF2 via its trans-proline 174-harboring hydrophobic interdomain linker sequence, blocking ubiquitin/KEAP1-mediated NRF2 degradation. X-ray co-crystal structure confirmed the direct PPIA–NRF2 interaction; ablation of PPIA promotes NRF2 ubiquitination and degradation. Cyclosporin A (CsA) impairs NRF2–PPIA interaction, inducing NRF2 degradation.\",\n      \"method\": \"X-ray co-crystallography, co-immunoprecipitation, ubiquitination assay, PPIA knockout/ablation, CsA treatment\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — X-ray co-crystal structure plus biochemical validation (Co-IP, ubiquitination assays, KO), multiple orthogonal methods\",\n      \"pmids\": [\"38830868\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Knockdown of CypA (PPIA) by RNAi in U2OS cells disrupts F-actin structure and decreases anchorage-independent growth, proliferation, and migration. CypA was found to bind N-WASP by in vitro and in vivo binding assays, and loss of CypA enhances N-WASP degradation, suggesting CypA stabilizes N-WASP to support N-WASP/Arp2/3-mediated F-actin polymerization. CsA treatment phenocopies CypA knockdown, implicating PPIase activity.\",\n      \"method\": \"RNAi knockdown, in vitro and in vivo binding assays (N-WASP), pulse-chase degradation assay, CsA treatment, F-actin imaging\",\n      \"journal\": \"Molecular and cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single Co-IP/pulldown plus RNAi phenotype, CsA confirmation; single lab\",\n      \"pmids\": [\"18704644\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"CypA-induced monocyte migration, MMP-9 expression, IL-6 and TNF-alpha release, and ERK1/2-mediated NF-κB activation are significantly inhibited when EMMPRIN (CD147) is blocked on monocytes, identifying CypA–EMMPRIN interaction as a key pro-inflammatory signaling pathway.\",\n      \"method\": \"Chemotaxis assay, ELISA, Western blot (ERK1/2-NF-κB), EMMPRIN blocking antibody\",\n      \"journal\": \"Atherosclerosis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — receptor blocking plus multiple downstream readouts; single lab\",\n      \"pmids\": [\"21035802\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CypA facilitates translocation of anthrax lethal factor fusion protein LF(N)DTA across endosomal membranes into the cytosol. In vitro, CypA bound directly to LF(N)DTA and DTA but not to LF. An antibody against CypA blocked release of LF(N)DTA from endosomal vesicles in vitro. Cyclosporin A (inhibiting CypA PPIase activity) prevented cytosolic delivery and protected cells from intoxication.\",\n      \"method\": \"In vitro binding assay (pulldown), anti-CypA antibody blocking, endosomal vesicle release assay, CsA inhibition, cell intoxication assay\",\n      \"journal\": \"Cellular microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding assay plus functional blocking antibody and pharmacological inhibition with orthogonal readouts\",\n      \"pmids\": [\"20946244\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CypA directly binds to IRF9 (the DNA-binding component of ISGF3) via its PPIase pocket; Cyp inhibitors (CsA, alisporivir, SCY-635) prevent IRF9–CypA complex formation. CypA binds specifically to the C-terminal IRF-association domain (IAD) of IRF9 but not to the DNA-binding or linker domains. HCV NS5A competes with IRF9 for CypA binding, preventing IRF9–CypA complex formation.\",\n      \"method\": \"Cellular and recombinant pulldown assays, domain mapping, competitive binding with NS5A\",\n      \"journal\": \"Journal of hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — reciprocal pulldowns with domain mapping and competitive inhibitor, single lab\",\n      \"pmids\": [\"22902549\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"GST pulldown and co-immunoprecipitation showed CypA interacts with NF-κB subunit p65/RelA. A CypA-binding consensus-like sequence was identified within p65 at N-terminal residues 170–176. CypA stabilized p65 protein and promoted its nuclear translocation, resulting in enhanced NF-κB transcriptional activity. NOTE: This paper has been RETRACTED.\",\n      \"method\": \"GST pulldown, co-immunoprecipitation, truncation and site-directed mutagenesis, luciferase assay, EMSA, immunofluorescence\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — paper is retracted; findings cannot be relied upon\",\n      \"pmids\": [\"25119989\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PPIA knockout mice have significantly less fat mass and smaller adipocytes than wild-type. PPIA silencing in 3T3L1 cells impairs adipocyte differentiation with reduced PPARG, C/EBPA, and C/EBPB expression at late differentiation stages; PPIA-KO MEFs show the same phenotype, rescued by PPIA re-expression. This identifies PPIA as a novel adipogenic factor.\",\n      \"method\": \"PPIA knockout mice, siRNA knockdown, gene overexpression/rescue, adipocyte differentiation assay, gene expression analysis\",\n      \"journal\": \"Obesity (Silver Spring, Md.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse phenotype corroborated by in vitro KD and rescue, multiple models\",\n      \"pmids\": [\"26347493\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Targeted disruption of both copies of mouse Ppia in embryonic stem (ES) cells demonstrated that CypA is not essential for mammalian cell viability or hematopoietic differentiation in vitro. The Ppia gene was characterized as consisting of 5 exons and 4 introns (~4.5 kb), mapping to chromosome 11. A 369-bp proximal promoter region containing TATA box and Sp1, AP-2, GATA, c-Myb, NF-IL-6 sites was sufficient for high-level reporter expression.\",\n      \"method\": \"Gene targeting (homologous recombination), ES cell knockout, reporter gene assay, hematopoietic differentiation\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout with functional validation; cell viability and differentiation assays, clear negative result\",\n      \"pmids\": [\"10964515\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Ppia−/− mice show low bone mineral density, reduced osteoblast numbers, and increased osteoclast numbers. Ppia−/− osteoblasts have decreased osteogenic differentiation; in osteoblasts, CypA is necessary for BMP-2-induced Smad phosphorylation. In osteoclasts, loss of CypA activates BtK and subsequently integrates with TRAF6 and/or c-fos signaling to induce NFATc1, increasing osteoclastic activity.\",\n      \"method\": \"Ppia−/− mouse model, osteoblast and osteoclast isolation and differentiation assay, BMP-2 signaling (Smad phosphorylation), overexpression and gene silencing, Western blot\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse model with cell-specific pathway dissection, single lab\",\n      \"pmids\": [\"26932182\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"STAT3 transcriptionally activates CypA expression by binding to a STAT3-responsive element (SRE) in the CypA promoter, as confirmed by ChIP and luciferase assays. STAT3-induced CypA expression mediates apoptosis of human umbilical vein endothelial cells in vitro.\",\n      \"method\": \"ChIP assay, luciferase reporter assay, RT-qPCR, immunostaining, cell viability and apoptosis assays\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus luciferase confirming STAT3-dependent transcription of CypA, functional apoptosis readout\",\n      \"pmids\": [\"31494257\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"HIF-1α directly binds to the hypoxia response element (HRE) in the CypA promoter and regulates CypA expression in pancreatic ductal adenocarcinoma cells, as shown by chromatin immunoprecipitation. Suppression or overexpression of HIF-1α correspondingly decreases or increases CypA mRNA and protein.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), HIF-1α overexpression/knockdown, RT-PCR, Western blot\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP assay with gain/loss-of-function validation; single lab\",\n      \"pmids\": [\"24662981\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Cryo-electron tomography and subtomogram averaging of native HIV-1 capsids revealed two distinct IP6 binding sites (at R18 and K25) and the structural modes of cyclophilin A interaction with HIV-1 capsomers. An all-atom model of the complete HIV-1 capsid was constructed.\",\n      \"method\": \"Cryo-electron tomography, subtomogram averaging, all-atom molecular modeling, free energy calculations\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — cryo-ET structural determination with free energy calculations and all-atom model; rigorous structural approach\",\n      \"pmids\": [\"34797722\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CypA directly interacts with influenza A virus matrix protein M1; this interaction was confirmed by pulldown and co-immunoprecipitation in vitro and in vivo. CypA restricts IAV replication by promoting ubiquitin-proteasome-mediated M1 degradation.\",\n      \"method\": \"Co-immunoprecipitation, pulldown, Western blot, viral replication assay\",\n      \"journal\": \"Proteomics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP/pulldown; interaction first described here for M1 with limited mechanistic follow-up in this paper (deeper mechanism in PMID 30328013)\",\n      \"pmids\": [\"30281201\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CypA interacts with SERPINH1 (identified by LC-MS/MS as a CypA-binding protein) in trophoblast cells. CypA promotes extracellular matrix (collagen I, fibronectin) production and inhibits epithelial-mesenchymal transition through the TGF-β/Smad3 signaling pathway. Silencing SERPINH1 reversed these CypA-induced effects.\",\n      \"method\": \"LC-MS/MS protein interaction discovery, stable OE/KD cell models, RNA-seq, Western blot, immunohistochemistry\",\n      \"journal\": \"Molecular and cellular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — MS-identified binding partner with siRNA functional validation and pathway analysis, single lab\",\n      \"pmids\": [\"35304192\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PARP3 directly interacts with Ppia and catalyzes mono ADP-ribosylation of Ppia at Glu140. Mutation of E140 inhibited inflammatory response, mono ADP-ribosylation, and secretion of Ppia. Ppia mediates PARP3-promoted macrophage inflammation via NF-κB signaling. PARP3 inhibitor ME0328 reduced NF-κB activation and inflammatory cytokines in ALI.\",\n      \"method\": \"Immunoprecipitation, site-directed mutagenesis (E140), RNA-seq, ELISA, Western blot, in vivo ALI model\",\n      \"journal\": \"Molecular medicine (Cambridge, Mass.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP confirming interaction, mutagenesis identifying modification site, functional KD and in vivo validation; single lab\",\n      \"pmids\": [\"40461998\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CypA stabilizes the ferroptosis suppressor SLC7A11 by competitively binding to its K37 site, blocking TRIM3-mediated ubiquitination and proteasomal degradation of SLC7A11. This interaction maintains cystine uptake and glutathione biosynthesis, attenuating ferroptosis induced by cisplatin/paclitaxel in NSCLC. CypA knockout or CsA treatment restores ferroptosis and reverses drug resistance.\",\n      \"method\": \"Co-immunoprecipitation, site-directed mutagenesis (K37), ubiquitination assay, CypA KO, CsA inhibition, in vitro and in vivo chemosensitivity assays\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with mutagenesis identifying binding site, KO and pharmacological inhibition with functional readouts; single lab\",\n      \"pmids\": [\"41203575\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The ALS-associated K76E mutation in PPIA significantly reduces its cis-trans isomerase enzyme activity without altering structure, monodispersity, or substrate recognition. Relaxation dispersion NMR revealed K76E disrupts key protein dynamics and an allosteric network essential for isomerase activity; the conformational exchange process is ~10-fold slower in K76E than wild-type, explaining reduced activity.\",\n      \"method\": \"Relaxation dispersion NMR, biochemical enzyme activity assay, biophysical characterization (structure, monodispersity), theoretical kinetic analysis\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR dynamics plus enzyme activity assay with mutagenesis; mechanistically rigorous single study\",\n      \"pmids\": [\"40587259\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CypA is recruited to orthopoxvirus factories and virions through interaction with the viral capsid protein L3, antagonizing TRIM5α-mediated antiviral restriction. This interaction is prevented by CsA and non-immunosuppressive CsA derivatives (alisporivir, NIM811). Both the proviral effect of CypA and the antiviral effect of CsA are dependent on TRIM5α.\",\n      \"method\": \"Cyclosporine A and derivative treatment, TRIM5α-dependent rescue assays, antiviral assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological and genetic epistasis in Nature publication; single lab but high-quality methods\",\n      \"pmids\": [\"37558876\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CypA directly interacts with TAF15, stabilizing it by suppressing proteasome-mediated degradation and promoting its nuclear entry. TAF15 in turn positively regulates STAT5A, which promotes CypA expression while miR-514a-3p directly binds the 3'-UTR of CypA to suppress its expression, forming a CypA/TAF15/STAT5A/miR-514a-3p feedback loop driving EMT and ovarian cancer metastasis.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, proteasome inhibition assay, 3'-UTR reporter, in vivo xenograft\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP/MS identification of TAF15, proteasomal stabilization assay, functional in vivo confirmation; single lab\",\n      \"pmids\": [\"39402372\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CypA colocalizes with pseudouridine synthase dyskerin in the nucleolus and directly interacts with dyskerin, which is the catalytic component of H/ACA RNPs. Dyskerin prolines (mutated in X-linked dyskeratosis congenita) are implicated as CypA client residues, suggesting CypA acts as a chaperone modulating dyskerin activity and RNP assembly.\",\n      \"method\": \"Colocalization imaging (immunofluorescence), direct interaction assay, structural analysis of proline mutations\",\n      \"journal\": \"Genes\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single colocalization and interaction assay; mechanistic follow-up limited; single lab\",\n      \"pmids\": [\"37761906\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CRISPR-KO and endogenous point-mutant (CypA unable to bind HIV-1 CA) cell lines demonstrated that cyclosporine A effects on HIV-1 infection are the direct result of blocking CA–CypA interactions, independent of CypA interactions with MX2 or other cellular proteins. Abrogation of CypA-CA interaction combined with loss of MX2 GTPase activity conferred enhanced MX2 antiviral activity and altered nucleoporin requirements.\",\n      \"method\": \"CRISPR-Cas9/AAV endogenous point mutation, CypA knockout, CsA treatment, HIV-1 infection assay, epistasis with MX2 GTPase mutants\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CRISPR endogenous mutagenesis with multiple CA and CypA variants providing clean genetic epistasis; rigorous controls\",\n      \"pmids\": [\"38512975\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"circ_005077 interacts with CypA and inhibits its ubiquitin-proteasome-mediated degradation, thereby promoting the interaction between CypA and p47phox to enhance NADPH oxidase activity and ROS generation, inducing ferroptosis in cardiomyocytes under lipotoxic conditions.\",\n      \"method\": \"RNA-protein interaction assay, Co-immunoprecipitation, ubiquitination assay, NADPH oxidase activity measurement, ferroptosis markers\",\n      \"journal\": \"Cardiovascular diabetology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — interaction demonstrated by Co-IP but primary focus is on the circRNA; mechanistic CypA findings are secondary; single lab\",\n      \"pmids\": [\"38622592\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CypA/MMP9 signaling pathway mediates ROS-induced blood-brain barrier disruption and delirium-like behavior in aged mice following anesthesia/surgery. ROS scavenging prevented CypA/MMP9 upregulation and BBB permeability increase; CypA inhibitor (CsA) abolished MMP9 elevation and reversed BBB damage, establishing CypA as upstream of MMP9 in this pathway.\",\n      \"method\": \"Western blot, CsA pharmacological inhibition, ROS scavenger (NAC), IgG permeability assay, behavioral tests\",\n      \"journal\": \"Frontiers in aging neuroscience\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — pharmacological inhibition only (no direct binding/mutagenesis); pathway position inferred from CsA and NAC treatment\",\n      \"pmids\": [\"36337710\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PPIA (CypA) is a peptidyl-prolyl cis-trans isomerase whose PPIase activity (dependent on catalytic pocket dynamics, disrupted by the ALS-associated K76E allosteric mutation) mediates protein folding and stabilization of multiple client proteins including NRF2 (blocking KEAP1/ubiquitin-mediated degradation via direct binding to a proline 174-containing linker), SLC7A11 (blocking TRIM3-mediated ubiquitination at K37), N-WASP, and TAF15; extracellular CypA acts as a cytokine/chemokine by binding directly to the ectodomain of CD147/EMMPRIN independent of PPIase activity to drive NF-κB/MAPK-mediated inflammation, leukocyte chemotaxis, and cancer stem cell signaling; intracellularly, CypA forms a pro-apoptotic complex with AIF (via AIF residues 370–394 near the PPIase pocket) that translocates to the nucleus to cause DNA degradation, and is also mono-ADP-ribosylated at Glu140 by PARP3 to promote NF-κB-dependent macrophage inflammation; in the context of HIV-1 and other viruses, CypA directly engages the viral capsid to modulate uncoating and TRIM5α-dependent restriction; and in bone biology, CypA supports osteoblast differentiation via BMP-2/Smad signaling while restraining osteoclastogenesis through the BtK/TRAF6/NFATc1 axis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PPIA (cyclophilin A, CypA) is a peptidyl-prolyl cis-trans isomerase whose catalytic activity depends on a defined dynamic allosteric network within its active-site pocket, as shown by the ALS-associated K76E mutation that selectively slows conformational exchange and impairs isomerase activity without altering overall structure [#20]. A dominant theme of its biology is the stabilization of client proteins against ubiquitin-mediated degradation: CypA directly binds the proline-174 interdomain linker of NRF2 to block KEAP1/ubiquitin-driven turnover (confirmed by co-crystal structure) [#4], competitively occupies the K37 ubiquitination site of SLC7A11 to prevent TRIM3-mediated degradation and restrain ferroptosis [#19], and stabilizes N-WASP [#5] and TAF15 [#22] to support actin-based motility and cancer cell EMT respectively. A second, PPIase-independent role is that of an extracellular pro-inflammatory mediator: CypA binds the ectodomain of CD147/EMMPRIN—via a surface overlapping but distinct from the PPIase pocket—to drive leukocyte chemotaxis and ERK1/2–NF-\\u03baB signaling [#0, #6]. Intracellularly, CypA forms a pro-apoptotic complex with AIF through AIF residues 370\\u2013394 binding near the CypA catalytic pocket, mediating mitochondrial AIF release and cell death [#1, #2]. CypA is itself transcriptionally controlled by STAT3, HIF-1\\u03b1, and TAF15/STAT5A inputs [#13, #14, #22] and is post-translationally mono-ADP-ribosylated at Glu140 by PARP3 to promote NF-\\u03baB-dependent macrophage inflammation [#18]. In viral infection, CypA directly engages viral capsids to modulate restriction and replication—binding the HIV-1 capsid to govern cyclosporine-sensitive infection and MX2/TRIM5\\u03b1 outcomes [#15, #24], the orthopoxvirus L3 protein to antagonize TRIM5\\u03b1 [#21], and influenza M1 to regulate its ubiquitination and nuclear export [#3]. CypA is dispensable for cell viability and hematopoietic differentiation [#11] but supports adipogenesis and bone homeostasis, promoting osteoblast differentiation via BMP-2/Smad while restraining osteoclastogenesis through a BtK/TRAF6/NFATc1 axis [#10, #12].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established whether CypA is essential, defining the baseline for all subsequent functional studies by showing it is dispensable for viability.\",\n      \"evidence\": \"Homozygous Ppia disruption in mouse ES cells with viability and hematopoietic differentiation assays\",\n      \"pmids\": [\"10964515\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Negative result in vitro does not address tissue-specific or stress-dependent functions\", \"Does not test redundancy with other cyclophilins\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defined the extracellular pro-inflammatory axis by showing CypA signals through EMMPRIN/CD147 to drive monocyte migration and NF-\\u03baB activation.\",\n      \"evidence\": \"Chemotaxis, ELISA, ERK1/2-NF-\\u03baB Western blot with EMMPRIN blocking antibody on monocytes\",\n      \"pmids\": [\"21035802\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor-blocking antibody does not map the molecular interface\", \"Does not resolve PPIase dependence\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Resolved whether CypA's chemotactic function requires its enzymatic activity, showing CD147 binding and chemotaxis are PPIase-independent and mediated by a distinct surface.\",\n      \"evidence\": \"NMR mapping, site-directed mutagenesis, and chemotaxis with the PPIase-inactive R55A mutant\",\n      \"pmids\": [\"21245143\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not establish in vivo relevance of identified residues\", \"Structure of the full CypA\\u2013CD147 ectodomain complex not solved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Mapped the pro-apoptotic CypA\\u2013AIF complex and showed its disruption blocks neuronal death, defining a druggable interface for AIF-dependent apoptosis.\",\n      \"evidence\": \"In vitro binding (KD 12 \\u03bcM), peptide inhibition, AIF translocation and cell death assays in HT-22 neurons with siRNA comparison\",\n      \"pmids\": [\"24434516\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PPIase catalysis acts on AIF not resolved\", \"In vivo neuroprotection not tested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Localized the AIF binding site to a surface near the CypA catalytic pocket overlapping the cyclosporin A site, structurally rationalizing the complex.\",\n      \"evidence\": \"NMR spectroscopy, biochemical binding, and molecular docking of AIF peptide onto CypA\",\n      \"pmids\": [\"28442737\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Model not validated by co-crystal structure\", \"Functional consequence of catalytic-pocket proximity untested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identified transcriptional control of CypA by HIF-1\\u03b1 via a promoter HRE, linking CypA expression to hypoxic tumor signaling.\",\n      \"evidence\": \"ChIP with HIF-1\\u03b1 gain/loss-of-function and RT-PCR/Western in pancreatic adenocarcinoma cells\",\n      \"pmids\": [\"24662981\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single tumor context\", \"Downstream functional output of induced CypA not dissected here\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Connected CypA to cytoskeletal dynamics by showing it stabilizes N-WASP to support F-actin polymerization, proliferation, and migration.\",\n      \"evidence\": \"RNAi, in vitro/in vivo N-WASP binding, pulse-chase degradation, CsA treatment, F-actin imaging in U2OS cells\",\n      \"pmids\": [\"18704644\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab and single Co-IP\", \"Direct enzymatic action on N-WASP not demonstrated\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstrated a metabolic role by identifying CypA as an adipogenic factor required for adipocyte differentiation.\",\n      \"evidence\": \"Ppia knockout mice, 3T3L1 siRNA, KO MEF rescue, and adipogenic gene expression\",\n      \"pmids\": [\"26347493\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular client mediating adipogenesis unidentified\", \"PPIase dependence not tested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Established opposing roles of CypA in bone, promoting osteoblast BMP-2/Smad signaling while restraining osteoclastogenesis via BtK/TRAF6/NFATc1.\",\n      \"evidence\": \"Ppia\\u2212/\\u2212 mice with cell-specific osteoblast/osteoclast differentiation and signaling assays\",\n      \"pmids\": [\"26932182\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular targets in each cell type not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showed STAT3 directly transactivates CypA, with induced CypA mediating endothelial apoptosis.\",\n      \"evidence\": \"ChIP, luciferase, RT-qPCR and apoptosis assays in HUVECs\",\n      \"pmids\": [\"31494257\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Apoptotic effector mechanism downstream of CypA not defined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Extended CypA's role to pathogen entry and antiviral signaling, showing it binds anthrax LF(N)DTA to enable cytosolic translocation and binds IRF9's IAD to support interferon signaling.\",\n      \"evidence\": \"In vitro binding, anti-CypA blocking, endosomal release and intoxication assays; domain-mapped pulldowns with NS5A competition\",\n      \"pmids\": [\"20946244\", \"22902549\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological significance of IRF9 interaction not established in vivo\", \"Catalytic versus scaffolding role unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined a mechanistic role for CypA in restricting influenza by modulating AIP4-dependent ubiquitination of viral M1 at K102/K104, controlling M1 nuclear export.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, mutagenesis, and virus rescue\",\n      \"pmids\": [\"30328013\", \"30281201\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CypA acts catalytically on M1 not shown\", \"In vivo antiviral relevance untested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Provided structural detail of CypA engagement with the native HIV-1 capsid lattice within an all-atom capsid model.\",\n      \"evidence\": \"Cryo-electron tomography, subtomogram averaging and free energy calculations\",\n      \"pmids\": [\"34797722\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not resolve functional outcome of binding in cells\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established CypA capsid binding as the key determinant of cyclosporine-sensitive viral restriction across viruses, antagonizing TRIM5\\u03b1 for orthopoxvirus and HIV-1.\",\n      \"evidence\": \"CsA/derivative treatment with TRIM5\\u03b1-dependent rescue (poxvirus L3) and CRISPR endogenous CypA/CA point-mutant epistasis with MX2 (HIV-1)\",\n      \"pmids\": [\"37558876\", \"38512975\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PPIase catalysis on capsid is required not fully resolved\", \"Mechanism of TRIM5\\u03b1 antagonism at molecular level incomplete\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined the structural basis of CypA-dependent NRF2 stabilization, showing direct binding to a proline-174 linker blocks KEAP1/ubiquitin-mediated degradation.\",\n      \"evidence\": \"X-ray co-crystallography, Co-IP, ubiquitination assay, PPIA ablation and CsA treatment\",\n      \"pmids\": [\"38830868\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether cis-trans isomerization of P174 is the mechanism not directly proven\", \"In vivo NRF2 pathway consequences not fully mapped\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified a CypA-stabilized TAF15 feedback loop driving ovarian cancer EMT and metastasis.\",\n      \"evidence\": \"Co-IP/MS, proteasome inhibition, 3'-UTR reporter and xenograft assays\",\n      \"pmids\": [\"39402372\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Direct enzymatic basis of TAF15 stabilization not shown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed CypA blocks ferroptosis by competitively shielding SLC7A11 K37 from TRIM3-mediated ubiquitination, linking CypA to chemoresistance.\",\n      \"evidence\": \"Co-IP, K37 mutagenesis, ubiquitination assay, CypA KO/CsA and in vivo chemosensitivity in NSCLC\",\n      \"pmids\": [\"41203575\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Catalytic versus competitive-binding contribution not separated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined PARP3-catalyzed mono-ADP-ribosylation of CypA at Glu140 as a switch enabling NF-\\u03baB-dependent macrophage inflammation and CypA secretion.\",\n      \"evidence\": \"Co-IP, E140 mutagenesis, RNA-seq, ELISA and in vivo acute lung injury model with PARP3 inhibitor\",\n      \"pmids\": [\"40461998\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"How E140 modification alters CypA secretion mechanistically unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrated that the ALS-associated K76E mutation impairs CypA isomerase activity by disrupting a dynamic allosteric network rather than the fold, mechanistically linking enzyme dynamics to disease.\",\n      \"evidence\": \"Relaxation dispersion NMR, enzyme activity assay and biophysical characterization\",\n      \"pmids\": [\"40587259\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not establish which client/folding defect drives ALS pathology\", \"In vivo phenotype of K76E not tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved which CypA functions strictly require its cis-trans isomerase catalysis versus scaffolding/competitive binding, and how a single catalytic surface coordinates its many client-stabilization, capsid, and inflammatory roles.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No systematic separation-of-function analysis across clients\", \"Unifying basis for client selectivity unknown\", \"In vivo contribution of individual interactions to disease undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016853\", \"supporting_discovery_ids\": [20]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [4, 19, 5, 22]},\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [4, 19]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1, 5]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 6, 18]},\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [23]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [22]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [6, 18, 0]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [3, 15, 24, 21]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [4, 19, 22]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [1, 19]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [6, 12]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CD147\", \"AIF\", \"NRF2\", \"SLC7A11\", \"N-WASP\", \"TAF15\", \"IRF9\", \"PARP3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}