UBQLN2 Mediates Autophagy-Independent Protein Aggregate Clearance by the Proteasome

Roland Hjerpe; John S. Bett; Matthew J. Keuss; Alexandra Solovyova; Thomas G. McWilliams; Clare Johnson; Indrajit Sahu; Joby Varghese; Nicola Wood; Melanie Wightman; Georgina Osborne; Gillian P. Bates; Michael H. Glickman; Matthias Trost; Axel Knebel; Francesco Marchesi; Thimo Kurz

doi:10.1016/j.cell.2016.07.001

UBQLN2 Mediates Autophagy-Independent Protein Aggregate Clearance by the Proteasome

Roland Hjerpe, John S. Bett, Matthew J. Keuss, Alexandra Solovyova, Thomas G. McWilliams, Clare Johnson, Indrajit Sahu, Joby Varghese, Nicola Wood, Melanie Wightman, Georgina Osborne, Gillian P. Bates, Michael H. Glickman, Matthias Trost, Axel Knebel, Francesco Marchesi, Thimo Kurz

Medical & Molecular Genetics

Research output: Contribution to journal › Article › peer-review

227 Citations (Scopus)

256 Downloads (Pure)

Abstract

Summary 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.

Original language	English
Journal	Cell
Early online date	28 Jul 2016
DOIs	https://doi.org/10.1016/j.cell.2016.07.001
Publication status	E-pub ahead of print - 28 Jul 2016

Access to Document

10.1016/j.cell.2016.07.001Licence: CC BY

UBQLN2 Mediates Autophagy_HJERPE_Accepted2July2016_GOLD VoRFinal published version, 4.45 MBLicence: CC BY

Cite this

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. (2016). UBQLN2 Mediates Autophagy-Independent Protein Aggregate Clearance by the Proteasome. Cell. Advance online publication. https://doi.org/10.1016/j.cell.2016.07.001

@article{09cc395df2184d7181a193d9cebdb4d6,

title = "UBQLN2 Mediates Autophagy-Independent Protein Aggregate Clearance by the Proteasome",

abstract = "Summary 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.",

author = "Roland Hjerpe and John S. Bett and Matthew J. Keuss and Alexandra Solovyova and Thomas G. McWilliams and Clare Johnson and Indrajit Sahu and Joby Varghese and Nicola Wood and Melanie Wightman and Georgina Osborne and Gillian P. Bates and Michael H. Glickman and Matthias Trost and Axel Knebel and Francesco Marchesi and Thimo Kurz",

year = "2016",

month = jul,

day = "28",

doi = "10.1016/j.cell.2016.07.001",

language = "English",

journal = "Cell",

issn = "0092-8674",

publisher = "Elsevier B.V.",

}

TY - JOUR

T1 - UBQLN2 Mediates Autophagy-Independent Protein Aggregate Clearance by the Proteasome

AU - Hjerpe, Roland

AU - Bett, John S.

AU - Keuss, Matthew J.

AU - Solovyova, Alexandra

AU - McWilliams, Thomas G.

AU - Johnson, Clare

AU - Sahu, Indrajit

AU - Varghese, Joby

AU - Wood, Nicola

AU - Wightman, Melanie

AU - Osborne, Georgina

AU - Bates, Gillian P.

AU - Glickman, Michael H.

AU - Trost, Matthias

AU - Knebel, Axel

AU - Marchesi, Francesco

AU - Kurz, Thimo

PY - 2016/7/28

Y1 - 2016/7/28

N2 - Summary 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.

AB - Summary 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.

U2 - 10.1016/j.cell.2016.07.001

DO - 10.1016/j.cell.2016.07.001

M3 - Article

SN - 0092-8674

JO - Cell

JF - Cell

ER -

UBQLN2 Mediates Autophagy-Independent Protein Aggregate Clearance by the Proteasome

Abstract

Access to Document

Fingerprint

Cite this