UBQLN2 mediates autophagy-independent protein aggregate clearance by the proteasome

Roland Hjerpe, John Bett (Lead / Corresponding author), Matthew Keuss, Alexandra Solovyova, Thomas 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 (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

209 Citations (Scopus)
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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 poly-ubiquitylated 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, called 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 languageEnglish
Pages (from-to)935-949
Number of pages15
Issue number4
Early online date28 Jul 2016
Publication statusPublished - 11 Aug 2016


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