PTMs in conversation: activity and function of deubiquitinating enzymes regulated via post-translational modifications

Abstract

Deubiquitinating enzymes (DUBs) constitute a diverse protein family and their impact on numerous biological and pathological processes has now been widely appreciated. Many DUB functions have to be tightly controlled within the cell, and this can be achieved in several ways, such as substrate-induced conformational changes, binding to adaptor proteins, proteolytic cleavage, and post-translational modifications (PTMs). This review is focused on the role of PTMs including monoubiquitination, sumoylation, acetylation, and phosphorylation as characterized and putative regulative factors of DUB function. Although this aspect of DUB functionality has not been yet thoroughly studied, PTMs represent a versatile and reversible method of controlling the role of DUBs in biological processes. In several cases PTMs might constitute a feedback mechanism insuring proper functioning of the ubiquitin proteasome system and other DUB-related pathways.

Fig. 1

PTMs in control of DUB activity exemplified by CYLD and UCH-L1. a Phosphorylation of CYLD impairs its deubiquitinating activity toward TRAF2. CYLD cleaves Lys⁶³-linked polyubiquitin chains from TRAF2, which results in negative regulation of the NF-κB pathway by inactivation of kinases JNK and IKK. IKKγ-mediated phosphorylation impairs its catalytic activity, in effect contributing to activation of JNK and IKK and positive regulation of NF-κB. b Monoubiquitination of UCH-L1 modulates its enzymatic function. UCH-L1 shortens conjugated polyubiquitin chains on the substrate proteins, and monoubiquitination of UCH-L1 hinders this activity by impairing its binding to ubiquitin. UCH-L1 is able to self-regulate its own ubiquitination status through auto-deubiquitination