Assembly and disassembly of branched ubiquitin chains

Abstract

Protein ubiquitylation is an essential post-translational modification that regulates nearly all aspects of eukaryotic cell biology. A diverse collection of ubiquitylation signals, including an extensive repertoire of polymeric ubiquitin chains, leads to a range of different functional outcomes for the target protein. Recent studies have shown that ubiquitin chains can be branched and that branched chains have a direct impact on the stability or the activity of the target proteins they are attached to. In this mini review, we discuss the mechanisms that control the assembly and disassembly of branched chains by the enzymes of the ubiquitylation and deubiquitylation machinery. Existing knowledge regarding the activities of chain branching ubiquitin ligases and the deubiquitylases responsible for cleaving branched chains is summarized. We also highlight new findings concerning the formation of branched chains in response to small molecules that induce the degradation of otherwise stable proteins and examine the selective debranching of heterotypic chains by the proteasome-bound deubiquitylase UCH37.

The emerging roles of non-canonical ubiquitination in proteostasis and beyond

“…Nuclear factor κB (NF-κB) inflammatory signaling is regulated by M1/K63 mixed ubiquitin chains, and K48/K63 branching of the mixed ubiquitin chains can inhibit their deubiquitination (Emmerich et al, 2013;Ohtake et al, 2016). Thus, diverse cellular pathways are regulated by the branched and mixed ubiquitin chains and by their responsible E2s/E3s (Gregor et al, 2023).…”