title: Trimming of ubiquitin chains by proteasome-associated deubiquitinating enzymes.
abstract: The proteasome generally recognizes substrate via its multiubiquitin chain followed by ATP-dependent unfolding and translocation of the substrate from the regulatory particle into the proteolytic core particle to be degraded. Substrate-bound ubiquitin groups are for the most part not delivered to the core particle and broken down together with substrate but instead recovered as intact free ubiquitin and ubiquitin chains. Substrate deubiquitination on the proteasome is mediated by three distinct deubiquitinating enzymes associated with the regulatory particle: RPN11, UCH37, and USP14. RPN11 cleaves at the base of the ubiquitin chain where it is linked to the substrate, whereas UCH37 and apparently USP14 mediate a stepwise removal of ubiquitin from the substrate by disassembling the chain from its distal tip. In contrast to UCH37 and USP14, RPN11 shows degradation-coupled activity; RPN11-mediated deubiquitination is apparently delayed until the proteasome is committed to degrade the substrate. Accordingly, RPN11-mediated deubiquitination promotes substrate degradation. In contrast, removal of ubiquitin prior to commitment could antagonize substrate degradation by promoting substrate dissociation from the proteasome. Emerging evidence suggests that USP14 and UCH37 can both suppress substrate degradation in this way. One line of study has shown that small molecule USP14 inhibitors can enhance proteasome function in cells, which is consistent with this model. Enhancing protein degradation could potentially have therapeutic applications for diseases involving toxic proteins that are proteasome substrates. However, the responsiveness of substrates to inhibition of proteasomal deubiquitinating enzymes may vary substantially. This substrate specificity and its mechanistic basis should be addressed in future studies.
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Min Jae
authors.initials: MJ
authors.lastname: Lee
authors.forename: Byung-Hoon
authors.initials: BH
authors.lastname: Lee
authors.forename: John
authors.initials: J
authors.lastname: Hanna
authors.forename: Randall W
authors.initials: RW
authors.lastname: King
authors.forename: Daniel
authors.initials: D
authors.lastname: Finley
mesh_terms: D000818:Animals; D002268:Carboxypeptidases / Q000378:metabolism; D010450:Endopeptidases / Q000378:metabolism; D006801:Humans; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D013379:Substrate Specificity; D043222:Ubiquitin Thiolesterase / Q000037:antagonists & inhibitors / Q000378:metabolism; D057149:Ubiquitinated Proteins / Q000378:metabolism*
chemical_list: D057149:Ubiquitinated Proteins; D002268:Carboxypeptidases; D010450:Endopeptidases; D043222:Ubiquitin Thiolesterase; D046988:Proteasome Endopeptidase Complex
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