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EMBO J. 2015 Sep 14;34(18):2363-82. doi: 10.15252/embj.201591245. Epub 2015 Aug 24.

RuvbL1 and RuvbL2 enhance aggresome formation and disaggregate amyloid fibrils.

Author information

1
Department of Biochemistry, Boston University School of Medicine, Boston, MA, USA.
2
Center for Biomedical Mass Spectrometry, Boston University School of Medicine, Boston, MA, USA.
3
INSERM U 1053, University of Bordeaux Segalen, Bordeaux, France.
4
Department of Biochemistry, Boston University School of Medicine, Boston, MA, USA Center for Biomedical Mass Spectrometry, Boston University School of Medicine, Boston, MA, USA.
5
School of Biology, Georgia Institute of Technology, Atlanta, GA, USA.
6
Laboratory of Amyloid Biology and Institute of Translational Biomedicine, St. Petersburg State University, St. Petersburg, Russia.
7
Department of Chemistry, University at Albany, State University of New York, Albany, NY, USA.
8
Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa, Oeiras, Portugal.
9
Instituto de Biologia Experimental e Tecnológica, Oeiras, Portugal.
10
Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa, Oeiras, Portugal Instituto de Biologia Experimental e Tecnológica, Oeiras, Portugal.
11
School of Biology, Georgia Institute of Technology, Atlanta, GA, USA Laboratory of Amyloid Biology and Institute of Translational Biomedicine, St. Petersburg State University, St. Petersburg, Russia yury.chernoff@biology.gatech.edu sherma1@bu.edu.
12
Department of Biochemistry, Boston University School of Medicine, Boston, MA, USA yury.chernoff@biology.gatech.edu sherma1@bu.edu.

Abstract

The aggresome is an organelle that recruits aggregated proteins for storage and degradation. We performed an siRNA screen for proteins involved in aggresome formation and identified novel mammalian AAA+ protein disaggregases RuvbL1 and RuvbL2. Depletion of RuvbL1 or RuvbL2 suppressed aggresome formation and caused buildup of multiple cytoplasmic aggregates. Similarly, downregulation of RuvbL orthologs in yeast suppressed the formation of an aggresome-like body and enhanced the aggregate toxicity. In contrast, their overproduction enhanced the resistance to proteotoxic stress independently of chaperone Hsp104. Mammalian RuvbL associated with the aggresome, and the aggresome substrate synphilin-1 interacted directly with the RuvbL1 barrel-like structure near the opening of the central channel. Importantly, polypeptides with unfolded structures and amyloid fibrils stimulated the ATPase activity of RuvbL. Finally, disassembly of protein aggregates was promoted by RuvbL. These data indicate that RuvbL complexes serve as chaperones in protein disaggregation.

KEYWORDS:

RuvbL; aggresome; amyloid; disaggregation

PMID:
26303906
PMCID:
PMC4570522
DOI:
10.15252/embj.201591245
[Indexed for MEDLINE]
Free PMC Article

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