UBQLN2 mediates autophagy-independent protein aggregate clearance by the proteasome

Hjerpe, R. et al. (2016) UBQLN2 mediates autophagy-independent protein aggregate clearance by the proteasome. Cell, 166(4), pp. 935-949. (doi: 10.1016/j.cell.2016.07.001) (PMID:27477512) (PMCID:PMC5003816)

Abstract

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.

• Item Type: Articles
• Additional Information: This work was supported by the Medical Research Council (MRC_MC_UU_12016/7), an ERC Starting Investigator Grant to T.K. (ERC_243019), a University of Glasgow Leadership Fellowship and Tenovus Scotland grant (to J.S.B.), the CDHI foundation (to G.B.), an Israel Science Foundation (ISF 909.14) grant (to M.H.G.),
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Marchesi, Dr Francesco and Kurz, Dr Thimo and Bett, Dr John and Hjerpe, Dr Roland
• Authors: Hjerpe, R., Bett, J. S., Keuss, M. J., Solovyova, A., McWilliams, T. G., Johnson, C., Sahu, I., Varghese, J., Wood, N., Wightman, M., Osborne, G., Bates, G. P., Glickman, M. H., Trost, M., Knebel, A., Marchesi, F., and Kurz, T.
• College/School: College of Medical Veterinary and Life Sciences > School of Molecular Biosciences; College of Medical Veterinary and Life Sciences > School of Biodiversity, One Health & Veterinary Medicine
• Journal Name: Cell
• Publisher: Elsevier (Cell Press)
• ISSN: 0092-8674
• ISSN (Online): 1097-4172
• Published Online: 28 July 2016
• Copyright Holders: Copyright © 2016 The Authors
• First Published: First published in Cell 166(4):935-949
• Publisher Policy: Reproduced under a creative commons license