Peptidylprolyl isomerase like 2 (PPIL2)

Peptidylprolyl isomerase like 2 (PPIL2) is a multidomain member of the cyclophilin family and functions primarily as an E3 ubiquitin-protein ligase rather than as an active peptidyl-prolyl isomerase, due to a key amino acid substitution in its catalytic domain. It contains an N-terminal U-box motif (required for ubiquitin ligase activity) and a C-terminal isomerase-like domain. PPIL2 plays a critical role in cell proliferation, particularly in erythropoiesis, by promoting the ubiquitination and degradation of the tumor suppressor protein p53, which enhances cell growth and survival. It is notably upregulated as a downstream target of the JAK2/STAT5 pathway and is strongly implicated in the pathogenesis of myeloproliferative neoplasms (MPNs). In addition, PPIL2 is a transient component of the minor spliceosome, suggesting a role in splicing of U12-type introns. Despite its similarity to other cyclophilins, it does not have typical cis-trans prolyl isomerase activity and displays poor binding to the cyclophilin inhibitor cyclosporin A. Experimental inhibition or loss of PPIL2 function leads to increased p53 protein, apoptosis, reduced cell proliferation and amelioration of MPN phenotypes in preclinical models.

Other names

Cyp-60Ring-type E3 ubiquitin-protein ligase PPIL2Cyclophilin-like protein Cyp-60hCyP-60U-box domain containing 7 (UBOX7)Probable inactive peptidyl-prolyl cis-trans isomerase-like 2Rotamase PPIL2Cyclophilin-60PPIaseRING-type E3 ubiquitin transferase isomerase-like 2CYC4CYP60

Inhibition of PPIL2 with cyclosporin A can upregulate p53 and suppress proliferation of JAK2-mutated erythroid/myeloid cells in models of myeloproliferative neoplasms, likely by disrupting PPIL2’s E3 ligase function. Cyclosporin A: general immunosuppressive agent, but its effect on PPIL2 is less direct due to altered binding pocket.