Alternative titles; symbols
HGNC Approved Gene Symbol: PPIA
Cytogenetic location: 7p13 Genomic coordinates (GRCh38): 7:44,796,681-44,803,117 (from NCBI)
Cyclophilin A, the major intracellular receptor for the immunosuppressant cyclosporin A (CsA), is a member of the immunophilin class of proteins, which all possess peptidyl-prolyl cis-trans isomerase activity and, therefore, are believed to be involved in protein folding and/or intracellular protein transport (summary by Willenbrink et al., 1995).
Cyclophilin is a specific high-affinity binding protein for the immunosuppressant agent cyclosporin A and has been shown to have dramatic effects on decreasing morbidity and increasing survival rates in human transplants. Liu et al. (1990) cloned human cDNA for T-cell CYPH and constructed an expression vector under control of the tac promoter for efficient expression in E. coli.
Luban et al. (1993) showed that cyclophilin A binds to the Gag protein of human immunodeficiency virus type 1 (HIV-1). This interaction can be inhibited by the immunosuppressant cyclosporin A and also by nonimmunosuppressive, cyclophilin A-binding cyclosporin A derivatives, which were also shown to exhibit potent anti-HIV-1 activity. Thus, cyclophilin A may have an essential function in HIV-1 replication.
Pushkarsky et al. (2001) identified CD147 (BSG; 109480) as a receptor for extracellular CYPA. They found that CD147 enhanced HIV-1 infection through interaction with CYPA incorporated into virions. Virus-associated CYPA coimmunoprecipitated with CD147 from infected cells, and antibody to CD147 inhibited HIV-1 entry. Viruses whose replication did not require CYPA were resistant to the inhibitory effect of anti-CD147 antibody. Pushkarsky et al. (2001) concluded that HIV-1 entry depends on an interaction between virus-associated CYPA and CD147 on a target cell.
Towers et al. (2003) demonstrated that HIV-1 sensitivity to restriction factors is modulated by CYPA. In certain nonhuman primate cells, the HIV-1 capsid protein (CA)-CYPA interaction is essential for restriction: HIV-1 infectivity is increased greater than 100-fold by cyclosporin A, a competitive inhibitor of the interaction, or by an HIV-1 CA mutation that disrupts CYPA binding. Conversely, disruption of CA-CYPA interaction in human cells reveals that CYPA protects HIV-1 from the Ref-1 restriction factor. Towers et al. (2003) concluded that their findings suggest that HIV-1 has coopted a host cell protein to counteract restriction factors expressed by human cells and this adaptation can confer sensitivity to restriction in unnatural hosts.
Manel et al. (2010) showed that, when dendritic cell resistance to infection is circumvented, HIV-1 induces dendritic cell maturation, an antiviral type I interferon response, and activation of T cells. This innate response is dependent on the interaction of newly synthesized HIV-1 capsid with cellular cyclophilin A (CYPA) and the subsequent activation of the transcription factor IRF3 (603734). Because the peptidylprolyl isomerase CYPA also interacts with HIV-1 capsid to promote infectivity, the results of Manel et al. (2010) indicated that capsid conformation has evolved under opposing selective pressures for infectivity versus furtiveness. Thus, a cell-intrinsic sensor for HIV-1 exists in dendritic cells and mediates an antiviral immune response, but it is not typically engaged owing to the absence of dendritic cell infection.
Using different Apoe (107741) transgenic mice, including mice with ablation and/or inhibition of CypA, Bell et al. (2012) showed that expression of Apoe4 and lack of murine Apoe, but not Apoe2 and Apoe3, leads to blood brain barrier breakdown by activating a proinflammatory CypA-Nfkb (164011)-Mmp9 (120361) pathway in pericytes. This, in turn, leads to neuronal uptake of multiple blood-derived neurotoxic proteins, and microvascular and cerebral blood flow reductions. Bell et al. (2012) showed that the vascular defects in Apoe-deficient and Apoe4-expressing mice precede neuronal dysfunction and can initiate neurodegenerative changes. Astrocyte-secreted Apoe3, but not Apoe4, suppressed the CypA-Nfkb-Mmp9 pathway in pericytes through a lipoprotein receptor. Bell et al. (2012) concluded that CypA is a key target for treating APOE4-mediated neurovascular injury and the resulting neuronal dysfunction and degeneration.
Rasaiyaah et al. (2013) showed that HIV-1 capsid mutants N74D and P90A, which are impaired for interaction with cofactors (CPSF6; 604979) and cyclophilins (NUP358, 601181 and CYPA), respectively, cannot replicate in primary human monocyte-derived macrophages because they trigger innate sensors leading to nuclear translocation of NFKB and IRF3, the production of soluble type I IFN, and induction of an antiviral state. Depletion of CPSF6 with short hairpin RNA expression allowed wildtype virus to trigger innate sensors and IFN production. In each case, suppressed replication was rescued by IFN-receptor blockade, demonstrating a role for IFN in restriction. IFN production is dependent on viral reverse transcription but not integration, indicating that a viral reverse transcription product comprises the HIV-1 pathogen-associated molecular pattern. Finally, Rasaiyaah et al. (2013) demonstrated that they could pharmacologically induce wildtype HIV-1 infection to stimulate IFN secretion and an antiviral state using a nonimmunosuppressive cyclosporine analog. The authors concluded that HIV-1 has evolved to use CPSF6 and cyclophilins to cloak its replication, allowing evasion of innate immune sensors and induction of a cell-autonomous innate immune response in primary human macrophages.
Using a panel of somatic rodent/human cell hybrids and PCR technology, Willenbrink et al. (1995) mapped the cyclophilin gene (designated PPIA) on chromosome 7 and 4 pseudogenes (PPIP2, PPIP3, PPIP4, and PPIP6) to chromosomes 14, 10, 18, and 3, respectively. Using chromosome 7 and chromosome 10 deletion hybrid panels, they further localized the PPIA coding gene to 7p13-p11.2, as confirmed by fluorescence in situ hybridization (FISH) analysis, and a pseudogene (PPIP3) to the region 10q11.2-q23.
Braaten et al. (1996) mapped the PPIA gene to 7p13 by FISH.
Crystal Structure
Fraser et al. (2009) introduced dual strategies of ambient temperature x-ray crystallographic data collection and automated electron density sampling to structurally unravel interconverting substrates of the human proline isomerase cyclophilin A. A conservative mutation outside the active site was designed to stabilize features of the previously hidden minor conformation. This mutation not only inverted the equilibrium between the substrates, but also caused large, parallel reductions in the conformational interconversion rates and the catalytic rate. Fraser et al. (2009) concluded that their studies introduced crystallographic approaches to define functional minor protein conformations and, in combination with NMR analysis of the enzyme dynamics in solution, show how collective motions directly contribute to the catalytic power of an enzyme.
Sayah et al. (2004) showed that knockdown of owl monkey CYPA by RNA interference (RNAi) correlated with suppression of anti-HIV-1 activity. However, reintroduction of CYPA to RNAi-treated cells did not restore antiviral activity. A search for additional RNAi targets identified TRIMCYP, an RNAi-responsive mRNA encoding a TRIM5 (608487)/CYPA fusion protein. TRIMCYP accounts for post-entry restriction of HIV-1 in owl monkeys and blocks HIV-1 infection when transferred to otherwise infectable human or rat cells. Sayah et al. (2004) suggested that TRIMCYP arose after the divergence of New and Old World primates when a LINE-1 retrotransposon catalyzed the insertion of a CYPA cDNA into the TRIM5 locus. They concluded that this was the first vertebrate example of a chimeric gene generated by this mechanism of exon shuffling.
Colgan et al. (2005) found that mice deficient in Cypa were resistant to immunosuppression by cyclosporine both in vitro and in vivo, as assessed by proliferation, IL2 (147680) secretion, signal transduction, and tumor rejection. Cypa-deficient mice remained sensitive to FK506. Colgan et al. (2005) concluded that CYPA is the primary mediator of immunosuppression by cyclosporine.
Bell, R. D., Winkler, E. A., Singh, I., Sagare, A. P., Deane, R., Wu, Z., Holtzman, D. M., Betsholtz, C., Armulik, A., Sallstrom, J., Berk, B. C., Zlokovic, B. V. Apolipoprotein E controls cerebrovascular integrity via cyclophilin A. Nature 485: 512-516, 2012. Note: Erratum: Nature 617: E12, 2023. [PubMed: 22622580] [Full Text: https://doi.org/10.1038/nature11087]
Braaten, D., Wellington, S., Warburton, D., Luban, J. Assignment of cyclophilin A (PPIA) to human chromosome band 7p13 by in situ hybridization. Cytogenet. Cell Genet. 74: 262 only, 1996. [PubMed: 8976380] [Full Text: https://doi.org/10.1159/000134430]
Colgan, J., Asmal, M., Yu, B., Luban, J. Cyclophilin A-deficient mice are resistant to immunosuppression by cyclosporine. J. Immun. 174: 6030-6038, 2005. [PubMed: 15879096] [Full Text: https://doi.org/10.4049/jimmunol.174.10.6030]
Fraser, J. S., Clarkson, M. W., Degnan, S. C., Erion, R., Kern, D., Alber, T. Hidden alternative structures of proline isomerase essential for catalysis. Nature 462: 669-673, 2009. [PubMed: 19956261] [Full Text: https://doi.org/10.1038/nature08615]
Liu, J., Albers, M. W., Chen, C.-M., Schreiber, S. L., Walsh, C. T. Cloning, expression, and purification of human cyclophilin in Escherichia coli and assessment of the catalytic role of cysteines by site-directed mutagenesis. Proc. Nat. Acad. Sci. 87: 2304-2308, 1990. [PubMed: 2179953] [Full Text: https://doi.org/10.1073/pnas.87.6.2304]
Luban, J., Bossolt, K. L., Franke, E. K., Kalpana, G. V., Goff, S. P. Human immunodeficiency virus type 1 gag protein binds to cyclophilins A and B. Cell 73: 1067-1078, 1993. [PubMed: 8513493] [Full Text: https://doi.org/10.1016/0092-8674(93)90637-6]
Manel, N., Hogstad, B., Wang, Y., Levy, D. E., Unutmaz, D., Littman, D. R. A cryptic sensor for HIV-1 activates antiviral innate immunity in dendritic cells. Nature 467: 214-217, 2010. Note: Erratum: Nature 470: 424 only, 2011. [PubMed: 20829794] [Full Text: https://doi.org/10.1038/nature09337]
Pushkarsky, T., Zybarth, G., Dubrovsky, L., Yurchenko, V., Tang, H., Guo, H., Toole, B., Sherry, B., Bukrinsky, M. CD147 facilitates HIV-1 infection by interacting with virus-associated cyclophilin A. Proc. Nat. Acad. Sci. 98: 6360-6365, 2001. [PubMed: 11353871] [Full Text: https://doi.org/10.1073/pnas.111583198]
Rasaiyaah, J., Tan, C. P., Fletcher, A. J., Price, A. J., Blondeau, C., Hilditch, L., Jacques, D. A., Selwood, D. L., James, L. C., Noursadeghi, M., Towers, G. J. HIV-1 evades innate immune recognition through specific cofactor recruitment. Nature 503: 402-405, 2013. [PubMed: 24196705] [Full Text: https://doi.org/10.1038/nature12769]
Sayah, D. M., Sokolskaja, E., Berthoux, L., Luban, J. Cyclophilin A retrotransposition into TRIM5 explains owl monkey resistance to HIV-1. Nature 430: 569-573, 2004. [PubMed: 15243629] [Full Text: https://doi.org/10.1038/nature02777]
Takahashi, N., Hayano, T., Suzuki, M. Peptidyl-prolyl cis-trans isomerase is the cyclosporin A-binding protein cyclophilin. Nature 337: 473-475, 1989. [PubMed: 2644542] [Full Text: https://doi.org/10.1038/337473a0]
Towers, G. J., Hatziioannou, T., Cowan, S., Goff, S. P., Luban, J., Bieniasz, P. D. Cyclophilin A modulates the sensitivity of HIV-1 to host restriction factors. Nature Med. 9: 1138-1143, 2003. [PubMed: 12897779] [Full Text: https://doi.org/10.1038/nm910]
Willenbrink, W., Halaschek, J., Schuffenhauer, S., Kunz, J., Steinkasserer, A. Cyclophilin A, the major intracellular receptor for the immunosuppressant cyclosporin A, maps to chromosome 7p11.2-p13: four pseudogenes map to chromosomes 3, 10, 14, and 18. Genomics 28: 101-104, 1995. [PubMed: 7590732] [Full Text: https://doi.org/10.1006/geno.1995.1112]