Affinage

PPIA

Peptidyl-prolyl cis-trans isomerase A · UniProt P62937

Length
165 aa
Mass
18.0 kDa
Annotated
2026-06-10
100 papers in source corpus 27 papers cited in narrative 27 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 2000 High

    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

    PMID:10964515

    Open questions at the time
    • Negative result in vitro does not address tissue-specific or stress-dependent functions
    • Does not test redundancy with other cyclophilins
  2. 2010 Medium

    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

    PMID:21035802

    Open questions at the time
    • Receptor-blocking antibody does not map the molecular interface
    • Does not resolve PPIase dependence
  3. 2011 High

    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

    PMID:21245143

    Open questions at the time
    • Does not establish in vivo relevance of identified residues
    • Structure of the full CypA–CD147 ectodomain complex not solved
  4. 2014 High

    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

    PMID:24434516

    Open questions at the time
    • Whether PPIase catalysis acts on AIF not resolved
    • In vivo neuroprotection not tested
  5. 2017 High

    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

    PMID:28442737

    Open questions at the time
    • Model not validated by co-crystal structure
    • Functional consequence of catalytic-pocket proximity untested
  6. 2014 Medium

    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

    PMID:24662981

    Open questions at the time
    • Single tumor context
    • Downstream functional output of induced CypA not dissected here
  7. 2008 Medium

    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

    PMID:18704644

    Open questions at the time
    • Single lab and single Co-IP
    • Direct enzymatic action on N-WASP not demonstrated
  8. 2015 Medium

    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

    PMID:26347493

    Open questions at the time
    • Molecular client mediating adipogenesis unidentified
    • PPIase dependence not tested
  9. 2016 Medium

    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

    PMID:26932182

    Open questions at the time
    • Direct molecular targets in each cell type not defined
    • Single lab
  10. 2019 Medium

    Showed STAT3 directly transactivates CypA, with induced CypA mediating endothelial apoptosis.

    Evidence ChIP, luciferase, RT-qPCR and apoptosis assays in HUVECs

    PMID:31494257

    Open questions at the time
    • Apoptotic effector mechanism downstream of CypA not defined
  11. 2012 Medium

    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

    PMID:20946244 PMID:22902549

    Open questions at the time
    • Physiological significance of IRF9 interaction not established in vivo
    • Catalytic versus scaffolding role unresolved
  12. 2018 High

    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

    PMID:30281201 PMID:30328013

    Open questions at the time
    • Whether CypA acts catalytically on M1 not shown
    • In vivo antiviral relevance untested
  13. 2021 High

    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

    PMID:34797722

    Open questions at the time
    • Does not resolve functional outcome of binding in cells
  14. 2023 High

    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)

    PMID:37558876 PMID:38512975

    Open questions at the time
    • Whether PPIase catalysis on capsid is required not fully resolved
    • Mechanism of TRIM5α antagonism at molecular level incomplete
  15. 2024 High

    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

    PMID:38830868

    Open questions at the time
    • Whether cis-trans isomerization of P174 is the mechanism not directly proven
    • In vivo NRF2 pathway consequences not fully mapped
  16. 2024 Medium

    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

    PMID:39402372

    Open questions at the time
    • Single lab
    • Direct enzymatic basis of TAF15 stabilization not shown
  17. 2025 Medium

    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

    PMID:41203575

    Open questions at the time
    • Single lab
    • Catalytic versus competitive-binding contribution not separated
  18. 2025 Medium

    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

    PMID:40461998

    Open questions at the time
    • Single lab
    • How E140 modification alters CypA secretion mechanistically unresolved
  19. 2025 High

    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

    PMID:40587259

    Open questions at the time
    • Does not establish which client/folding defect drives ALS pathology
    • In vivo phenotype of K76E not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 4 GO:0098772 molecular function regulator activity 2 GO:0140313 molecular sequestering activity 2 GO:0016853 isomerase activity 1
Localization
GO:0005576 extracellular region 3 GO:0005829 cytosol 2 GO:0005634 nucleus 1 GO:0005730 nucleolus 1
Pathway
R-HSA-1643685 Disease 4 R-HSA-168256 Immune System 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-162582 Signal Transduction 2 R-HSA-5357801 Programmed Cell Death 2
Partners
AIFCD147IRF9N-WASPNRF2PARP3SLC7A11TAF15

Evidence

Reading pass · 27 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2011 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. NMR spectroscopy, site-directed mutagenesis, chemotaxis assay, binding assays with PPIase-inactive mutant The Journal of biological chemistry High 21245143
2014 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. In vitro binding assay (KD measurement), peptide inhibition of complex formation, mitochondrial membrane potential assay, CypA-siRNA knockdown, cell death assay Cell death & disease High 24434516
2017 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. NMR spectroscopy, molecular modeling/docking, biochemical binding studies Scientific reports High 28442737
2018 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. Co-immunoprecipitation, ubiquitination assays, site-directed mutagenesis, virus rescue assay, Western blot Virologica Sinica High 30328013
2024 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. X-ray co-crystallography, co-immunoprecipitation, ubiquitination assay, PPIA knockout/ablation, CsA treatment Nature communications High 38830868
2008 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. RNAi knockdown, in vitro and in vivo binding assays (N-WASP), pulse-chase degradation assay, CsA treatment, F-actin imaging Molecular and cellular biochemistry Medium 18704644
2010 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. Chemotaxis assay, ELISA, Western blot (ERK1/2-NF-κB), EMMPRIN blocking antibody Atherosclerosis Medium 21035802
2012 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. In vitro binding assay (pulldown), anti-CypA antibody blocking, endosomal vesicle release assay, CsA inhibition, cell intoxication assay Cellular microbiology Medium 20946244
2012 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. Cellular and recombinant pulldown assays, domain mapping, competitive binding with NS5A Journal of hepatology Medium 22902549
2014 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. GST pulldown, co-immunoprecipitation, truncation and site-directed mutagenesis, luciferase assay, EMSA, immunofluorescence PloS one Low 25119989
2015 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. PPIA knockout mice, siRNA knockdown, gene overexpression/rescue, adipocyte differentiation assay, gene expression analysis Obesity (Silver Spring, Md.) Medium 26347493
2000 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. Gene targeting (homologous recombination), ES cell knockout, reporter gene assay, hematopoietic differentiation Genomics High 10964515
2016 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. Ppia−/− mouse model, osteoblast and osteoclast isolation and differentiation assay, BMP-2 signaling (Smad phosphorylation), overexpression and gene silencing, Western blot Scientific reports Medium 26932182
2019 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. ChIP assay, luciferase reporter assay, RT-qPCR, immunostaining, cell viability and apoptosis assays Cellular signalling Medium 31494257
2014 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. Chromatin immunoprecipitation (ChIP), HIF-1α overexpression/knockdown, RT-PCR, Western blot PloS one Medium 24662981
2021 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. Cryo-electron tomography, subtomogram averaging, all-atom molecular modeling, free energy calculations Science advances High 34797722
2018 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. Co-immunoprecipitation, pulldown, Western blot, viral replication assay Proteomics Low 30281201
2022 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. LC-MS/MS protein interaction discovery, stable OE/KD cell models, RNA-seq, Western blot, immunohistochemistry Molecular and cellular endocrinology Medium 35304192
2025 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. Immunoprecipitation, site-directed mutagenesis (E140), RNA-seq, ELISA, Western blot, in vivo ALI model Molecular medicine (Cambridge, Mass.) Medium 40461998
2025 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. Co-immunoprecipitation, site-directed mutagenesis (K37), ubiquitination assay, CypA KO, CsA inhibition, in vitro and in vivo chemosensitivity assays Advanced science (Weinheim, Baden-Wurttemberg, Germany) Medium 41203575
2025 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. Relaxation dispersion NMR, biochemical enzyme activity assay, biophysical characterization (structure, monodispersity), theoretical kinetic analysis Biochemistry High 40587259
2023 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. Cyclosporine A and derivative treatment, TRIM5α-dependent rescue assays, antiviral assays Nature Medium 37558876
2024 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. Co-immunoprecipitation, mass spectrometry, proteasome inhibition assay, 3'-UTR reporter, in vivo xenograft Oncogene Medium 39402372
2023 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. Colocalization imaging (immunofluorescence), direct interaction assay, structural analysis of proline mutations Genes Low 37761906
2024 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. CRISPR-Cas9/AAV endogenous point mutation, CypA knockout, CsA treatment, HIV-1 infection assay, epistasis with MX2 GTPase mutants PLoS pathogens High 38512975
2024 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. RNA-protein interaction assay, Co-immunoprecipitation, ubiquitination assay, NADPH oxidase activity measurement, ferroptosis markers Cardiovascular diabetology Low 38622592
2024 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. Western blot, CsA pharmacological inhibition, ROS scavenger (NAC), IgG permeability assay, behavioral tests Frontiers in aging neuroscience Low 36337710

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 Evolution of a TRIM5-CypA splice isoform in old world monkeys. PLoS pathogens 159 18389077
2005 Restriction of human immunodeficiency virus type 1 by TRIM-CypA occurs with rapid kinetics and independently of cytoplasmic bodies, ubiquitin, and proteasome activity. Journal of virology 138 16306627
2004 Aflatoxin biosynthesis cluster gene cypA is required for G aflatoxin formation. Applied and environmental microbiology 121 15528514
2010 Pro-inflammatory activities induced by CyPA-EMMPRIN interaction in monocytes. Atherosclerosis 98 21035802
1999 Using an enzyme linked immunosorbent assay (ELISA) and a protein phosphatase inhibition assay (PPIA) for the detection of microcystins and nodularins. Natural toxins 82 11122533
2011 Cyclophilin A (CyPA) induces chemotaxis independent of its peptidylprolyl cis-trans isomerase activity: direct binding between CyPA and the ectodomain of CD147. The Journal of biological chemistry 71 21245143
2021 Structure of native HIV-1 cores and their interactions with IP6 and CypA. Science advances 57 34797722
2014 Inhibition of the AIF/CypA complex protects against intrinsic death pathways induced by oxidative stress. Cell death & disease 57 24434516
2007 Regulatory polymorphisms in the cyclophilin A gene, PPIA, accelerate progression to AIDS. PLoS pathogens 56 17590083
2002 Peptidylprolyl isomerase A (PPIA) as a preferred internal control over GAPDH and beta-actin in quantitative RNA analyses. BioTechniques 55 11962599
2014 RETRACTED: Cyclophilin A (CypA) interacts with NF-κB subunit, p65/RelA, and contributes to NF-κB activation signaling. PloS one 54 25119989
2010 Role of CypA and Hsp90 in membrane translocation mediated by anthrax protective antigen. Cellular microbiology 53 20946244
2023 The exoprotein Gbp of Fusobacterium nucleatum promotes THP-1 cell lipid deposition by binding to CypA and activating PI3K-AKT/MAPK/NF-κB pathways. Journal of advanced research 51 37100345
2010 Knockdown of CypA inhibits interleukin-8 (IL-8) and IL-8-mediated proliferation and tumor growth of glioblastoma cells through down-regulated NF-κB. Journal of neuro-oncology 44 20454998
2005 Altered HIV-1 Gag protein interactions with cyclophilin A (CypA) on the acquisition of H219Q and H219P substitutions in the CypA binding loop. The Journal of biological chemistry 44 16275650
2015 The Novel Extracellular Cyclophilin A (CyPA) - Inhibitor MM284 Reduces Myocardial Inflammation and Remodeling in a Mouse Model of Troponin I -Induced Myocarditis. PloS one 39 25894208
2000 Isolation, characterization and targeted disruption of mouse ppia: cyclophilin A is not essential for mammalian cell viability. Genomics 38 10964515
2012 Deregulation of XPC and CypA by cyclosporin A: an immunosuppression-independent mechanism of skin carcinogenesis. Cancer prevention research (Philadelphia, Pa.) 37 22846842
2024 PPIA dictates NRF2 stability to promote lung cancer progression. Nature communications 36 38830868
2023 TRIM5α restricts poxviruses and is antagonized by CypA and the viral protein C6. Nature 34 37558876
2014 CypA, a gene downstream of HIF-1α, promotes the development of PDAC. PloS one 33 24662981
2009 Cyclophilin A (CypA) is associated with the inflammatory infiltration and alveolar bone destruction in an experimental periodontitis. Biochemical and biophysical research communications 32 19968957
2014 CD147 and CD98 complex-mediated homotypic aggregation attenuates the CypA-induced chemotactic effect on Jurkat T cells. Molecular immunology 31 25089027
2020 Interleukin 37 (IL-37) Reduces High Glucose-Induced Inflammation, Oxidative Stress, and Apoptosis of Podocytes by Inhibiting the STAT3-Cyclophilin A (CypA) Signaling Pathway. Medical science monitor : international medical journal of experimental and clinical research 29 32931486
2019 Role of CyPA in cardiac hypertrophy and remodeling. Bioscience reports 29 31825469
2017 Structural and biochemical insights of CypA and AIF interaction. Scientific reports 28 28442737
2021 Identification of Celastrol as a Novel Therapeutic Agent for Pulmonary Arterial Hypertension and Right Ventricular Failure Through Suppression of Bsg (Basigin)/CyPA (Cyclophilin A). Arteriosclerosis, thrombosis, and vascular biology 27 33472404
2016 Melatonin attenuates angiotensin II-induced cardiomyocyte hypertrophy through the CyPA/CD147 signaling pathway. Molecular and cellular biochemistry 26 27590243
2022 Reactive oxygen species contribute to delirium-like behavior by activating CypA/MMP9 signaling and inducing blood-brain barrier impairment in aged mice following anesthesia and surgery. Frontiers in aging neuroscience 24 36337710
2012 HCV NS5A and IRF9 compete for CypA binding. Journal of hepatology 24 22902549
2008 Knockdown endogenous CypA with siRNA in U2OS cells results in disruption of F-actin structure and alters tumor phenotype. Molecular and cellular biochemistry 24 18704644
2011 Surface lipoprotein PpiA of Streptococcus mutans suppresses scavenger receptor MARCO-dependent phagocytosis by macrophages. Infection and immunity 23 21986627
2023 Cyclophilin A Inhibitors Suppress Proliferation and Induce Apoptosis of MKN45 Gastric Cancer Stem-like Cells by Regulating CypA/CD147-Mediated Signaling Pathway. International journal of molecular sciences 22 36902161
2021 Ppia is the most stable housekeeping gene for qRT-PCR normalization in kidneys of three Pkd1-deficient mouse models. Scientific reports 22 34611276
2019 PPIA, HPRT1, and YWHAZ Genes Are Suitable for Normalization of mRNA Expression in Long-Term Expanded Human Mesenchymal Stem Cells. BioMed research international 22 31240211
2015 PPIA is a novel adipogenic factor implicated in obesity. Obesity (Silver Spring, Md.) 21 26347493
2008 Cyanobacterial LPS antagonist (CyP)-a novel and efficient inhibitor of Escherichia coli LPS-induced cytokine response in the pig. Molecular immunology 21 18571239
2024 Circ_005077 accelerates myocardial lipotoxicity induced by high-fat diet via CyPA/p47PHOX mediated ferroptosis. Cardiovascular diabetology 20 38622592
2018 CypA Regulates AIP4-Mediated M1 Ubiquitination of Influenza A Virus. Virologica Sinica 20 30328013
2017 Selective targeting p53WT lung cancer cells harboring homozygous p53 Arg72 by an inhibitor of CypA. Oncogene 18 28394340
2015 PpiA antigen specific immune response is a potential biomarker for latent tuberculosis infection. Tuberculosis (Edinburgh, Scotland) 18 26546406
2020 Detachment Activated CyPA/CD147 Induces Cancer Stem Cell Potential in Non-stem Breast Cancer Cells. Frontiers in cell and developmental biology 17 33195186
2019 STAT3-CyPA signaling pathway in endothelial cell apoptosis. Cellular signalling 17 31494257
2018 Global Profiling of PknG Interactions Using a Human Proteome Microarray Reveals Novel Connections with CypA. Proteomics 17 30281201
2003 High frequency of alternative splicing of human genes participating in the HIV-1 life cycle: a model using TSG101, betaTrCP, PPIA, INI1, NAF1, and PML. Journal of acquired immune deficiency syndromes (1999) 17 14526201
2013 Involvement of lipoprotein PpiA of Streptococcus gordonii in evasion of phagocytosis by macrophages. Molecular oral microbiology 16 23734737
2012 PpiA, a surface PPIase of the cyclophilin family in Lactococcus lactis. PloS one 16 22442694
2008 A search for cyclophilin-A gene (PPIA) variation and its contribution to the risk of atherosclerosis and myocardial infarction. International journal of immunogenetics 15 18321308
2022 miR-15a and miR-20b sensitize hepatocellular carcinoma cells to sorafenib through repressing CDC37L1 and consequent PPIA downregulation. Cell death discovery 14 35760798
2019 Positive Correlation between Activated CypA/CD147 Signaling and MMP-9 Expression in Mice Inflammatory Periapical Lesion. BioMed research international 14 30949512
2018 The roles of CyPA and CD147 in cardiac remodelling. Experimental and molecular pathology 14 29772453
2016 Cyclophilin A (CypA) Plays Dual Roles in Regulation of Bone Anabolism and Resorption. Scientific reports 14 26932182
2001 The Aspergillus niger cypA gene encodes a cyclophilin that mediates sensitivity to the immunosuppressant cyclosporin A. Molecular genetics and genomics : MGG 14 11810223
2021 CypA: A Potential Target of Tumor Radiotherapy and/or Chemotherapy. Current medicinal chemistry 13 33121398
2015 Discovery of Novel Small Molecule Anti-HCV Agents via the CypA Inhibitory Mechanism Using O-Acylation-Directed Lead Optimization. Molecules (Basel, Switzerland) 13 26053489
2023 Natural Cyclophilin A Inhibitors Suppress the Growth of Cancer Stem Cells in Non-Small Cell Lung Cancer by Disrupting Crosstalk between CypA/CD147 and EGFR. International journal of molecular sciences 12 37298389
2022 CyPA interacts with SERPINH1 to promote extracellular matrix production and inhibit epithelial-mesenchymal transition of trophoblast via enhancing TGF-β/Smad3 pathway in preeclampsia. Molecular and cellular endocrinology 11 35304192
2022 Chronic cerebral hypoperfusion alters the CypA-EMMPRIN-gelatinase pathway: Implications for vascular dementia. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 11 36537035
2015 PPIA rs6850: A > G single-nucleotide polymorphism is associated with raised plasma cyclophilin A levels in patients with coronary artery disease. Molecular and cellular biochemistry 11 26702934
2018 Binding mode of AIF(370-394) peptide to CypA: insights from NMR, label-free and molecular docking studies. The Biochemical journal 10 29891613
2017 Simvastatin attenuated rat thoracic aorta remodeling by decreasing ROCK2‑mediated CyPA secretion and CD147‑ERK1/2‑cyclin pathway. Molecular medicine reports 10 28983618
2024 An apolipoprotein E receptor mimetic peptide decreases blood-brain barrier permeability following intracerebral hemorrhage by inhibiting the CypA/MMP-9 signaling pathway via LRP1 activation. International immunopharmacology 9 39486173
2022 TBP, PPIA, YWHAZ and EF1A1 Are the Most Stably Expressed Genes during Osteogenic Differentiation. International journal of molecular sciences 9 35457075
2022 The adhesion protein of Mycoplasma genitalium inhibits urethral epithelial cell apoptosis through CypA-CD147 activating PI3K/ Akt/NF-κB pathway. Applied microbiology and biotechnology 9 36066653
2017 CyPA and Emmprin play a role in peri-implantitis. Clinical implant dentistry and related research 9 29057571
2024 Virus specificity and nucleoporin requirements for MX2 activity are affected by GTPase function and capsid-CypA interactions. PLoS pathogens 8 38512975
2024 CypA/TAF15/STAT5A/miR-514a-3p feedback loop drives ovarian cancer metastasis. Oncogene 8 39402372
2023 Mycoplasma genitalium Protein of Adhesion Suppresses T Cell Activation via CypA-CaN-NFAT Pathway. Microbiology spectrum 7 37074201
2021 Relevance of AIF/CypA Lethal Pathway in SH-SY5Y Cells Treated with Staurosporine. International journal of molecular sciences 7 35008690
2020 Citron Rho-Interacting Serine/Threonine Kinase Promotes HIF1a-CypA Signaling and Growth of Human Pancreatic Adenocarcinoma. BioMed research international 7 32185224
2020 Design, synthesis, structural analysis and biochemical studies of stapled AIF(370-394) analogues as ligand of CypA. Biochimica et biophysica acta. General subjects 7 32861757
2019 A cyclophilin A (CypA) from Apostichopus japonicus modulates NF-κB translocation as a cofactor. Fish & shellfish immunology 7 31740398
2019 CYPA promotes the progression and metastasis of serous ovarian cancer (SOC) in vitro and in vivo. Journal of ovarian research 7 31783885
2015 CyPA-CD147-ERK1/2-cyclin D2 signaling pathway is upregulated during rat left ventricular hypertrophy. Sheng li xue bao : [Acta physiologica Sinica] 7 26300251
2023 The effects of CypA on apoptosis: potential target for the treatment of diseases. Applied microbiology and biotechnology 6 38159118
2020 Single-nucleotide Polymorphism rs17860041 A/C in the Promoter of the PPIA Gene is Associated with Susceptibility to Kawasaki Disease in Chinese Children. Immunological investigations 6 32079425
2008 Evasion from CypA- and APOBEC-mediated restrictions is insufficient for HIV-1 to efficiently grow in simian cells. Microbes and infection 6 19056509
2004 Cloning and characterisation of the immunophilin X-CypA in Xenopus laevis. Gene expression patterns : GEP 6 15533818
1991 Phenotype versus genotype of the 19 kD peptido-glycan associated protein of Legionella (PpIA), among Legionellae and other gram-negative bacteria. Microbial pathogenesis 6 1816489
2025 PPIA enhances cell growth and metastasis through CD147 in oral cancer. Archives of biochemistry and biophysics 5 39921142
2022 PPIA, HPRT1, and YWHAZ are suitable reference genes for quantitative polymerase chain reaction assay of the hypothalamic-pituitary-gonadal axis in sows. Animal bioscience 5 35507843
2014 TRIMe7-CypA, an alternative splicing isoform of TRIMCyp in rhesus macaque, negatively modulates TRIM5α activity. Biochemical and biophysical research communications 5 24613845
1999 Transcriptional analysis of the cyclophilin A gene (cypA) of Streptomyces chrysomallus. FEMS microbiology letters 5 10483721
2025 Discovery of Novel Oxazolo[4,3-f]purine Derivatives as Antitumor Agents through PPIA Interaction. Journal of medicinal chemistry 4 40012358
2022 MxB Disrupts Hepatitis C Virus NS5A-CypA Complex: Insights From a Combined Theoretical and Experimental Approach. Frontiers in microbiology 4 35369502
2020 Cyclophilin A (CyPA) as a Novel Biomarker for Early Detection of Diabetic Nephropathy in an Animal Model. Diabetes, metabolic syndrome and obesity : targets and therapy 4 33116728
2018 EMMPRIN-CypA contributes to the inflammatory processes in human periodontitis through infiltrating CD68+ inflammatory cells. International journal of clinical and experimental pathology 4 31949770
2025 Mycoplasma genitalium protein of adhesion inhibits human urethral epithelial cells apoptosis via CypA/PI3K/AKT/mTOR-dependent autophagy. Frontiers in microbiology 3 40207157
2025 PARP3 promotes macrophage inflammation via mono ADP ribosylation of Ppia Glu140. Molecular medicine (Cambridge, Mass.) 3 40461998
2025 CypA Mediates Non-Small Cell Lung Cancer Chemoresistance by Attenuating Ferroptosis via Stabilizing SLC7A11. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 3 41203575
2023 New Insights into Dyskerin-CypA Interaction: Implications for X-Linked Dyskeratosis Congenita and Beyond. Genes 3 37761906
2011 Restriction of the felid lentiviruses by a synthetic feline TRIM5-CypA fusion. Veterinary immunology and immunopathology 3 21813188
2025 Fusobacterium nucleatum drives gastric cancer metastasis via Gbp-CypA-NF-κB-mediated CXCL8 crosstalk between tumor cells and mast cells. Cell communication and signaling : CCS 2 41316398
2024 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. Journal of neuroscience research 2 38361405
2023 Virus specificity and nucleoporin requirements for MX2 activity are affected by GTPase function and capsid-CypA interactions. bioRxiv : the preprint server for biology 2 38014352
2010 [Progress of CypA and lung cancer-related research]. Zhongguo fei ai za zhi = Chinese journal of lung cancer 2 20704827
2025 A Disease-Associated Mutation Impedes PPIA through Allosteric Dynamics Modulation. Biochemistry 1 40587259
2025 Multidimensional pan-cancer analysis reveals the impact of PPIA on tumor epigenetic modifications and immune regulation. Scientific reports 1 40594293
2024 PPIA, HRPT1, and PGK1 genes as the appropriate combination for RT-qPCR normalization in alveolar and femoral bone remodeling in olanzapine-treated rats. Acta pharmaceutica (Zagreb, Croatia) 1 39279526
2024 PPIA-coExp: Discovering Context-Specific Biomarkers Based on Protein-Protein Interactions, Co-Expression Networks, and Expression Data. International journal of molecular sciences 1 39684321

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