Branched ubiquitin chain binding and deubiquitination by UCH37 facilitate proteasome clearance of stress-induced inclusions
Branched ubiquitin chain binding and deubiquitination by UCH37 facilitate proteasome clearance of stress-induced inclusions
Abstract UCH37, also known as UCHL5, is a highly conserved deubiquitinating enzyme (DUB) that associates with the 26S proteasome. Recently it was reported that UCH37 activity is stimulated by branched ubiquitin chain architectures. To understand how UCH37 achieves its unique debranching specificity, we performed biochemical and NMR structural analyses and found that UCH37 is activated by contacts with the hydrophobic patches of both distal ubiquitins that emanate from a branched ubiquitin. In addition, RPN13, which recruits UCH37 to the proteasome, further enhances branched-chain specificity by restricting linear ubiquitin chains from having access to the UCH37 active site. In cultured human cells under conditions of proteolytic stress, we show that substrate clearance by the proteasome is promoted by both binding and deubiquitination of branched polyubiquitin by UCH37. Proteasomes containing UCH37(C88A), which is catalytically inactive, aberrantly retain polyubiquitinated species as well as the RAD23B substrate shuttle factor, suggesting a defect in recycling of the proteasome. These findings provide a foundation to understand how proteasome degradation of substrates modified by a unique ubiquitin chain architecture is aided by a DUB.
Yao Tingting、Song Aixin、Dortch Jeremy、Martinez Sarah Bollinger、Yu Clinton、Huang Lan、Curtiss Justin、Abeykoon Dulith、Hazlett Zachary、Fushman David、Dillon Andrew、Hill Christopher P.、Cohen Robert E.
Department of Biochemistry and Molecular Biology, Colorado State UniversityDepartment of Biochemistry and Molecular Biology, Colorado State UniversityDepartment of Biochemistry and Molecular Biology, Colorado State UniversityDepartment of Biochemistry and Molecular Biology, Colorado State UniversityDepartment of Physics and Biophysics, University of CaliforniaDepartment of Physics and Biophysics, University of CaliforniaDepartment of Biochemistry and Molecular Biology, Colorado State UniversityDepartment of Chemistry and Biochemistry, University of Maryland, College ParkDepartment of Biochemistry and Molecular Biology, Colorado State UniversityDepartment of Biochemistry, University of Utah School of MedicineDepartment of Biochemistry and Molecular Biology, Colorado State UniversityDepartment of Biochemistry, University of Utah School of MedicineDepartment of Biochemistry and Molecular Biology, Colorado State University
生物化学分子生物学基础医学
Yao Tingting,Song Aixin,Dortch Jeremy,Martinez Sarah Bollinger,Yu Clinton,Huang Lan,Curtiss Justin,Abeykoon Dulith,Hazlett Zachary,Fushman David,Dillon Andrew,Hill Christopher P.,Cohen Robert E..Branched ubiquitin chain binding and deubiquitination by UCH37 facilitate proteasome clearance of stress-induced inclusions[EB/OL].(2025-03-28)[2025-04-26].https://www.biorxiv.org/content/10.1101/2021.08.17.456719.点此复制
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