UBQLN2 Mediates Autophagy-Independent Protein Aggregate Clearance by the Proteasome.

Autor:	Hjerpe R; Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, Davidson Building, Henry Wellcome Lab of Cell Biology, University of Glasgow, G12 8QQ Glasgow, UK; The MRC Protein Phosphorylation and Ubiquitylation Unit, The Sir James Black Centre, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, Scotland., Bett JS; Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, Davidson Building, Henry Wellcome Lab of Cell Biology, University of Glasgow, G12 8QQ Glasgow, UK; The MRC Protein Phosphorylation and Ubiquitylation Unit, The Sir James Black Centre, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, Scotland. Electronic address: johnsbett@yahoo.co.uk., Keuss MJ; The MRC Protein Phosphorylation and Ubiquitylation Unit, The Sir James Black Centre, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, Scotland., Solovyova A; Newcastle University Protein and Proteome Analysis, Devonshire Building, Devonshire Terrace, Newcastle upon Tyne NE1 7RU, UK., McWilliams TG; The MRC Protein Phosphorylation and Ubiquitylation Unit, The Sir James Black Centre, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, Scotland., Johnson C; The MRC Protein Phosphorylation and Ubiquitylation Unit, The Sir James Black Centre, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, Scotland., Sahu I; Department of Biology, Technion-Israel Institute of Technology, 32000 Haifa, Israel., Varghese J; The MRC Protein Phosphorylation and Ubiquitylation Unit, The Sir James Black Centre, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, Scotland., Wood N; The MRC Protein Phosphorylation and Ubiquitylation Unit, The Sir James Black Centre, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, Scotland., Wightman M; The MRC Protein Phosphorylation and Ubiquitylation Unit, The Sir James Black Centre, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, Scotland., Osborne G; Department of Medical and Molecular Genetics, King's College London, 8th Floor Tower Wing, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK., Bates GP; Department of Medical and Molecular Genetics, King's College London, 8th Floor Tower Wing, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK., Glickman MH; Department of Biology, Technion-Israel Institute of Technology, 32000 Haifa, Israel., Trost M; The MRC Protein Phosphorylation and Ubiquitylation Unit, The Sir James Black Centre, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, Scotland., Knebel A; The MRC Protein Phosphorylation and Ubiquitylation Unit, The Sir James Black Centre, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, Scotland., Marchesi F; School of Veterinary Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, 464 Bearsden Road, Glasgow G61 1QH, UK., Kurz T; Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, Davidson Building, Henry Wellcome Lab of Cell Biology, University of Glasgow, G12 8QQ Glasgow, UK; The MRC Protein Phosphorylation and Ubiquitylation Unit, The Sir James Black Centre, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, Scotland. Electronic address: thimo.kurz@glasgow.ac.uk.
Jazyk:	angličtina
Zdroj:	Cell [Cell] 2016 Aug 11; Vol. 166 (4), pp. 935-949. Date of Electronic Publication: 2016 Jul 28.
DOI:	10.1016/j.cell.2016.07.001
Abstrakt:	Clearance of misfolded and aggregated proteins is central to cell survival. Here, we describe a new pathway for maintaining protein homeostasis mediated by the proteasome shuttle factor UBQLN2. The 26S proteasome degrades polyubiquitylated substrates by recognizing them through stoichiometrically bound ubiquitin receptors, but substrates are also delivered by reversibly bound shuttles. We aimed to determine why these parallel delivery mechanisms exist and found that UBQLN2 acts with the HSP70-HSP110 disaggregase machinery to clear protein aggregates via the 26S proteasome. UBQLN2 recognizes client-bound HSP70 and links it to the proteasome to allow for the degradation of aggregated and misfolded proteins. We further show that this process is active in the cell nucleus, where another system for aggregate clearance, autophagy, does not act. Finally, we found that mutations in UBQLN2, which lead to neurodegeneration in humans, are defective in chaperone binding, impair aggregate clearance, and cause cognitive deficits in mice. (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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