Branched ubiquitin chain binding and deubiquitination by UCH37 facilitate proteasome clearance of stress-induced inclusions

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 (Ub) chain architectures. To understand how UCH37 achieves its unique debranching specificity, we...

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Autores principales:	Aixin Song, Zachary Hazlett, Dulith Abeykoon, Jeremy Dortch, Andrew Dillon, Justin Curtiss, Sarah Bollinger Martinez, Christopher P Hill, Clinton Yu, Lan Huang, David Fushman, Robert E Cohen, Tingting Yao
Formato:	article
Lenguaje:	EN
Publicado:	eLife Sciences Publications Ltd 2021
Materias:	UCH37 UCHL5 ubiquitin DUB branched ubiquitin chain proteasome Medicine R Science Q Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/9c4ca33ec53a49a49f85fa2ba7b8f54f
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spelling	oai:doaj.org-article:9c4ca33ec53a49a49f85fa2ba7b8f54f2021-12-01T15:19:27ZBranched ubiquitin chain binding and deubiquitination by UCH37 facilitate proteasome clearance of stress-induced inclusions10.7554/eLife.727982050-084Xe72798https://doaj.org/article/9c4ca33ec53a49a49f85fa2ba7b8f54f2021-11-01T00:00:00Zhttps://elifesciences.org/articles/72798https://doaj.org/toc/2050-084XUCH37, 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 (Ub) chain architectures. To understand how UCH37 achieves its unique debranching specificity, we performed biochemical and Nuclear Magnetic Resonance (NMR) structural analyses and found that UCH37 is activated by contacts with the hydrophobic patches of both distal Ubs that emanate from a branched Ub. In addition, RPN13, which recruits UCH37 to the proteasome, further enhances branched-chain specificity by restricting linear Ub 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 for the next round of substrate processing. These findings provide a foundation to understand how proteasome degradation of substrates modified by a unique Ub chain architecture is aided by a DUB.Aixin SongZachary HazlettDulith AbeykoonJeremy DortchAndrew DillonJustin CurtissSarah Bollinger MartinezChristopher P HillClinton YuLan HuangDavid FushmanRobert E CohenTingting YaoeLife Sciences Publications LtdarticleUCH37UCHL5ubiquitinDUBbranched ubiquitin chainproteasomeMedicineRScienceQBiology (General)QH301-705.5ENeLife, Vol 10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	UCH37 UCHL5 ubiquitin DUB branched ubiquitin chain proteasome Medicine R Science Q Biology (General) QH301-705.5
spellingShingle	UCH37 UCHL5 ubiquitin DUB branched ubiquitin chain proteasome Medicine R Science Q Biology (General) QH301-705.5 Aixin Song Zachary Hazlett Dulith Abeykoon Jeremy Dortch Andrew Dillon Justin Curtiss Sarah Bollinger Martinez Christopher P Hill Clinton Yu Lan Huang David Fushman Robert E Cohen Tingting Yao Branched ubiquitin chain binding and deubiquitination by UCH37 facilitate proteasome clearance of stress-induced inclusions
description	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 (Ub) chain architectures. To understand how UCH37 achieves its unique debranching specificity, we performed biochemical and Nuclear Magnetic Resonance (NMR) structural analyses and found that UCH37 is activated by contacts with the hydrophobic patches of both distal Ubs that emanate from a branched Ub. In addition, RPN13, which recruits UCH37 to the proteasome, further enhances branched-chain specificity by restricting linear Ub 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 for the next round of substrate processing. These findings provide a foundation to understand how proteasome degradation of substrates modified by a unique Ub chain architecture is aided by a DUB.
format	article
author	Aixin Song Zachary Hazlett Dulith Abeykoon Jeremy Dortch Andrew Dillon Justin Curtiss Sarah Bollinger Martinez Christopher P Hill Clinton Yu Lan Huang David Fushman Robert E Cohen Tingting Yao
author_facet	Aixin Song Zachary Hazlett Dulith Abeykoon Jeremy Dortch Andrew Dillon Justin Curtiss Sarah Bollinger Martinez Christopher P Hill Clinton Yu Lan Huang David Fushman Robert E Cohen Tingting Yao
author_sort	Aixin Song
title	Branched ubiquitin chain binding and deubiquitination by UCH37 facilitate proteasome clearance of stress-induced inclusions
title_short	Branched ubiquitin chain binding and deubiquitination by UCH37 facilitate proteasome clearance of stress-induced inclusions
title_full	Branched ubiquitin chain binding and deubiquitination by UCH37 facilitate proteasome clearance of stress-induced inclusions
title_fullStr	Branched ubiquitin chain binding and deubiquitination by UCH37 facilitate proteasome clearance of stress-induced inclusions
title_full_unstemmed	Branched ubiquitin chain binding and deubiquitination by UCH37 facilitate proteasome clearance of stress-induced inclusions
title_sort	branched ubiquitin chain binding and deubiquitination by uch37 facilitate proteasome clearance of stress-induced inclusions
publisher	eLife Sciences Publications Ltd
publishDate	2021
url	https://doaj.org/article/9c4ca33ec53a49a49f85fa2ba7b8f54f
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Branched ubiquitin chain binding and deubiquitination by UCH37 facilitate proteasome clearance of stress-induced inclusions

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