HUMAN PARAOXONASE 2 (PON2): regulation under stressing conditions

PON1, PON2, and PON3 belong to a family of lactone hydrolyzing enzymes endowed with various substrate specificities. PON2 shows the highest hydrolytic activity toward many acyl-homoserine lactones and has antiROS activity. Recent findings have highlighted the importance of PON2 in oxidative stress control, inhibition of apoptosis, and in the progression of various types of malignancies (1). Starting from biocomputing and by exploitation of biochemical, molecular and mass spectrometry approaches, we discovered a new pathway that controls PON2 expression in HeLa cells (2) via 1) a putative mRNA operon mechanism, involving the Wilms tumor 1 associated protein (WTAP) and the E3 ubiquitin ligase (E3UbL) baculoviral IAP repeat-containing 3 (BIRC3); 2) differential expression of PON2 isoforms with different activities; c) post-translational regulation by several Post-Translational Modifications (PTMs) (3). Of note, WTAP has been reported to bind the 3'-UTR of cyclin A2, which enhances its stability thereby regulating G2/M cell cycle transition, and to induce cancer, if deregulated. BIRC3 is an E3UbL involved in apoptosis via caspase 3 (CASP3) inhibition. These findings have led us to propose a working model for the regulation of PON2 expression (2). We report here additional results and a novel extended model of PON2 regulation at multiple levels.