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UBQLN2 Mediates Autophagy-Independent Protein Aggregate Clearance by the Proteasome

Lookup NU author(s): Dr Alexandra Solovyova

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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.

Publication metadata

Author(s): Hjerpe R, Bett JS, Keuss MJ, Solovyova A, McWilliams TG, Johnson C, Sahu I, Varghese J, Wood N, Wightman M, Osborne G, Bates GP, Glickman MH, Trost M, Knebel A, Marchesi F, Kurz T

Publication type: Article

Publication status: Published

Journal: Cell

Year: 2016

Volume: 166

Issue: 4

Pages: 935-949

Print publication date: 11/08/2016

Online publication date: 28/07/2016

Acceptance date: 02/07/2016

Date deposited: 26/10/2016

ISSN (print): 0092-8674

ISSN (electronic): 1097-4172

Publisher: Cell Press

URL: http://dx.doi.org/10.1016/j.cell.2016.07.001

DOI: 10.1016/j.cell.2016.07.001

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