Deubiquitinating enzyme regulation of the p53 pathway: A lesson from Otub1

Abstract

Deubiquitination has emerged as an important mechanism of p53 regulation. A number of deubiquitinating enzymes (DUBs) from the ubiquitin-specific protease family have been shown to regulate the p53-MDM2-MDMX networks. We recently reported that Otub1, a DUB from the OTU-domain containing protease family, is a novel p53 regulator. Interestingly, Otub1 abrogates p53 ubiquitination and stabilizes and activates p53 in cells independently of its deubiquitinating enzyme activity. Instead, it does so by inhibiting the MDM2 cognate ubiquitin-conjugating enzyme (E2) UbcH5. Otub1 also regulates other biological signaling through this non-canonical mechanism, suppression of E2, including the inhibition of DNA-damage-induced chromatin ubiquitination. Thus, Otub1 evolves as a unique DUB that mainly suppresses E2 to regulate substrates. Here we review the current progress made towards the understanding of the complex regulation of the p53 tumor suppressor pathway by DUBs, the biological function of Otub1 including its positive regulation of p53, and the mechanistic insights into how Otub1 suppresses E2.

Keywords: p53, MDM2, Ubiquitination, Deubiquitinating enzymes, Otub1, Cell cycle, Apoptosis

Core tip: p53 is tightly regulated by dynamic ubiquitination and deubiquitination. A number of deubiquitinating enzymes (DUBs) have been shown to regulate p53 stability and activity by either directly deubiquitinating p53 or indirectly deubiquitinating its regulators. We recently discovered that Otub1, an OTU family DUB, stabilizes and activates p53 via distinct and non-canonical mechanism wherein it suppresses the MDM2 cognate ubiquitin-conjugating enzymes UbcH5. Here we review the current progress made towards the understanding of the Otub1 functions as a potent E2 inhibitor and the underlying mechanisms.