Protein phosphatase 3 catalytic subunit alpha (PPP3CA) (PPP3CA)

Calcineurin A, specifically the alpha isoform (PPP3CA), is the catalytic subunit of the calcium-dependent serine/threonine phosphatase calcineurin (UniProt: P16298). It plays a pivotal role in the immune system by dephosphorylating the Nuclear Factor of Activated T-cells (NFAT), which then translocates to the nucleus to induce the transcription of cytokines like interleukin-2 (IL-2) (PubMed: 23160471). In the context of engineered EBV-specific T cells, Calcineurin A is a primary target for modification to confer resistance to calcineurin inhibitors (CNIs) such as tacrolimus and cyclosporine (PubMed: 28814475). This engineering is crucial for patients undergoing hematopoietic stem cell or solid organ transplantation who require CNIs to prevent graft-versus-host disease or organ rejection but also need functional EBV-specific T cells to combat EBV-driven lymphoproliferative disorders. By introducing mutations like CNA12 or using gene-editing techniques, these T cells can maintain their effector functions despite the presence of systemic immunosuppression (PubMed: 23160471). Consequently, Calcineurin A serves as both a traditional drug target for immunosuppression and a strategic site for genetic enhancement in adoptive immunotherapy.

Other names

Calcineurin APPP3CACALNACALNA1CNA1Protein phosphatase 2B catalytic subunit alpha

Calcineurin inhibitors (CNIs) bind to intracellular immunophilins (FKBP12 for tacrolimus; cyclophilin for cyclosporine) to form a complex that inhibits the phosphatase activity of Calcineurin A, thereby preventing the dephosphorylation of NFAT and subsequent T-cell activation (PubMed: 23160471).