The USP19 deubiquitinase regulates the stability of c-IAP1 and c-IAP2

The inhibitors of Apoptosis (IAPs) are critical regulators of Apoptosis and Other fundamental cellular processes. Many IAPs are RING domain-containing ubiquitin E3 Ligases that control the stability of their interacting proteins. However, how IAP stability is regulated remains unclear. Here we report that USP19, a deubiquitinating Enzyme, interacts with cellular IAP 1 (c-IAP1) and c-IAP2. Knockdown of USP19 decreases levels of both c-IAPs, whereas overexpression of USP19 results in a marked increase in c-IAP levels. USP19 effectively removes ubiquitin from c-IAPs in vitro, but it stabilizes c-IAPs in vivo mainly through deubiquitinase-independent mechanisms. The Deubiquitinase activity is involved in the stabilization of USP19 itself, which is facilitated by USP19 self-association. Functionally, knockdown of USP19 enhances TNFα-induced Caspase activation and Apoptosis in a c-IAP1 and 2-dependent manner. These results suggest that the self-ubiquitin Ligase activity of c-IAPs is inhibited by USP19 and implicate deubiquitinating Enzymes in the regulation of IAP stability.