RuvbL1 and RuvbL2 enhance aggresome formation and disaggregate amyloid fibrils

• DOI: 10.15252/embj.201591245
• Publication Date: 2015-08-25T01:19:58Z
• Authors: Nava Zaarur; Xiaobin Xu; Patrick Lestienne; Anatoli B Meriin; Mark McComb; Catherine E Costello; Gary P Newnam; Rakhee Ganti; Nina V Romanova; Maruda Shanmugasu...; Sara TN Silva; Tiago M Bandeiras; Pedro M Matias; Kirill S Lobachev; Igor K Lednev; Yury O Chernoff; Michael Y Sherman
• Keywords: Organelles; 0301 basic medicine; Amyloid; 03 medical and health sciences; HEK293 Cells; DNA Helicases; ATPases Associated with Diverse Cellular Activities; Humans; Nerve Tissue Proteins; Carrier Proteins; Heat-Shock Proteins; HeLa Cells

AbstractThe 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.