Ubiquitylation is a post-translational modification that regulates a wide range of cellular pathways including protein degradation, autophagy, mitophagy, cell signaling, DNA damage response, and protein trafficking. This post-translational modification is characterized by covalent attachment of ubiquitin to lysine residues on target proteins by E3 ubiquitin ligases. These enzymes can catalyze both mono- and polyubiquitylation of target substrates. Because of the presence of multiple ubiquitylation acceptor sites on ubiquitin, polyubiquitin chains differing by linkage type and branching patterns can be generated. Post-translational modifications on ubiquitin including glutamine deamidation, lysine SUMOylation, lysine acetylation, and serine, threonine, and tyrosine phosphorylation add to the range of ubiquitin structures that can be synthesized in cells. Recently, ADP-ribosylation was discovered as a new post-translational modification on ubiquitin in two different biological contexts. The bacterial SidE proteins ADP-ribosylate ubiquitin to activate it for a unique mode of ubiquitylation. The human Dtx3L (E3 ubiquitin ligase)/Parp9 (ADP-ribosyltransferase) complex ADP-ribosylates ubiquitin which inhibits conjugation. In this review, we describe the discovery of ubiquitin ADP-ribosylation in the bacterial context, provide an overview of the biological roles of Dtx3L/Parp9, and discuss how NAD+ levels and ubiquitin ADP-ribosylation could regulate the E3 output of Dtx3L/Parp9.
Part of the book: Ubiquitin Proteasome System