Branched ubiquitin code: from basic biology to targeted protein degradation

Protein ubiquitylation regulates numerous pathways, and the diverse information encoded by various forms of ubiquitylation is known as the ubiquitin code. Recent studies revealed that branched ubiquitin chains are abundant in mammalian cells and regulate important pathways. They include proteasomal degradation of misfolded and disease-causing proteins, regulation of NF-κB signalling and apoptotic cell fate decisions. Targeted protein degradation through chemical degraders emerged as a transformative therapeutic paradigm aimed at inducing the disappearance of unwanted cellular proteins. To further improve the efficacy of target degradation and expand its applications, understanding the molecular mechanism of degraders’ action from the view of ubiquitin code biology is required. In this review, I discuss the roles of the ubiquitin code in biological pathways and in chemically induced targeted protein degradation by focusing on the branched ubiquitin codes that we have characterized.