Regulation of the proteasome by ubiquitin chain editing

Abstract

Error‐correction mechanisms in protein synthesis are well‐known. In an interesting analogy, the proteasome contains activities that can remodel, or edit, multiubiquitin chains on substrates. These activities regulate degradation rates in yeast and mammals. The effects are powerful but vary in strength from substrate to substrate. The main editing factors are the deubiquitinating enzyme Ubp6 and the ubiquitin ligase Hul5 (in yeast). Ubp6 suppresses degradation while Hul5 promotes it. Regulation of degradation may reflect that more heavily ubiquitinated substrates bind the proteasome more avidly. These factors can transduce signals to modulate proteasome activity positively or negatively. For example, UBP6 is induced when ubiquitin levels fall, while HUL5 is not. In addition to modifying ubiquitin chains, both factors regulate degradation noncatalytically. Hul5's noncatalytic effect is apparently to suppress Ubp6 deubiquitinating activity. Also, of the 910 residues in Hul5, only a short 13‐residue segment at the N‐terminus is required for the noncatalytic effect. The deubiquitinating activity of Usp14 (the mammalian ortholog of Ubp6) can be suppressed by small‐molecule inhibitors identified by high‐throughput screening. These compounds allow one to enhance the degradation rates of many proteins, including toxic proteins such as mutant forms of tau that have been implicated in neurodegeneration.