30 January 2018
Fumiaki Ohtake, Ph.D.（Laboratory Protein Metabolism） published a paper on “K63 ubiquitylation triggers proteasomal degradation by seeding branched ubiquitin chains” in PNAS.
Regulated protein degradation in response to cellular context plays critical roles in cellular physiology. In eukaryotes, regulated proteolysis is largely mediated by the ubiquitin–proteasome system. Ubiquitin can be linked through lysine residues to yield polyubiquitin chains However, the ubiquitin signals that lead to proteasomal degradation are not fully understood. Previously, we found that ubiquitin chains can be ‘branched’ at lysines 48 and 63 (K48 and K63). In this study, we analyzed role of K48/K63 branched ubiquitin chains in proteasome-mediated protein degradation.
By using quantitative analyses, we found that K48/K63 branched ubiquitin chains are involved in proteasome-mediated protein degradation. Moreover, we identified two ubiquitin ligases, ITCH and UBR5, as enzymes cooperatively assembling branched ubiquitin chains. These results reveal a new ubiquitin-dependent pathway leading to the proteasome. Because the ubiquitin–proteasome system is a central regulator of various biological and pathological pathways including inflammation, neurodegeneration, and tumor growth, selective modulation of branched ubiquitin chains will represent a new strategy for control of these pathways.