Peptidyl-prolyl cis-trans isomerase A (Cyclophilin A) (PPIA)

Peptidyl-prolyl cis-trans isomerase A (PPIA), commonly known as Cyclophilin A, is a ubiquitous cytosolic enzyme that belongs to the immunophilin family and plays a critical role in protein folding and trafficking (UniProt P62937). It functions as a molecular chaperone by catalyzing the cis-trans isomerization of proline imidic peptide bonds, which is a rate-limiting step in protein folding. PPIA is the primary intracellular receptor for the immunosuppressive drug Ciclosporin; upon binding, the resulting Ciclosporin-PPIA complex inhibits the phosphatase activity of Calcineurin (StatPearls). This inhibition prevents the activation of the Nuclear Factor of Activated T-cells (NFAT), thereby blocking the production of pro-inflammatory cytokines such as Interleukin-2 that are essential for T-cell proliferation. Beyond its role in immunosuppression, PPIA is involved in the replication cycles of several viruses, including HIV-1 and Hepatitis C, making it a target for antiviral research (PubMed). Clinically, targeting this pathway is fundamental in preventing organ transplant rejection and managing autoimmune diseases like rheumatoid arthritis and psoriasis. However, therapeutic modulation of this target via Ciclosporin is associated with significant safety concerns, most notably dose-dependent nephrotoxicity and systemic hypertension (NIH).

Other names

PPIACyclophilin ACYPACYPHRotamase APeptidyl-prolyl cis-trans isomerase A

Ciclosporin binds to Peptidyl-prolyl cis-trans isomerase A (Cyclophilin A) to form a complex that inhibits the phosphatase activity of Calcineurin (Protein phosphatase 2B), thereby blocking the dephosphorylation and nuclear translocation of the Nuclear Factor of Activated T-cells (NFAT) and preventing the transcription of Interleukin-2 (StatPearls).