期刊
EMBO JOURNAL
卷 34, 期 18, 页码 2363-2382出版社
WILEY
DOI: 10.15252/embj.201591245
关键词
aggresome; amyloid; disaggregation; RuvbL
资金
- US National Institutes of Health [P41 GM104603, HHSN268201000031C, R01 GM086890, R01GM093294]
- National Science Foundation [CHE-1152752, MCB-0818122]
- Fundacao para a Ciencia e Tecnologia (Portugal) [PTDC/BBB-BEP/1724/2012, PEst-OE/EQB/LA0004/2011]
- Russian Science Foundation [14-50-00069]
- St. Petersburg State University [1.50.2218.2013, IAS 1.42.1284.2014]
- Fundação para a Ciência e a Tecnologia [PTDC/BBB-BEP/1724/2012] Funding Source: FCT
- Division Of Chemistry
- Direct For Mathematical & Physical Scien [1152752] Funding Source: National Science Foundation
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.
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