title: Chaperone-mediated 26S proteasome remodeling facilitates free K63 ubiquitin chain production and aggresome clearance.
abstract: Efficient elimination of misfolded proteins by the proteasome system is critical for proteostasis. Inadequate proteasome capacity can lead to aberrant aggregation of misfolded proteins and inclusion body formation, a hallmark of neurodegenerative disease. The proteasome system cannot degrade aggregated proteins; however, it stimulates autophagy-dependent aggregate clearance by producing unanchored lysine (K)63-linked ubiquitin chains via the proteasomal deubiquitinating enzyme Poh1. The canonical function of Poh1, which removes ubiquitin chains en bloc from proteasomal substrates prior to their degradation, requires intact 26S proteasomes. Here we present evidence that during aggresome clearance, 20S proteasomes dissociate from protein aggregates, while Poh1 and selective subunits of 19S proteasomes are retained. The dissociation of 20S proteasome components requires the molecular chaperone Hsp90. Hsp90 inhibition suppresses 26S proteasome remodeling, unanchored ubiquitin chain production, and aggresome clearance. Our results suggest that 26S proteasomes undergo active remodeling to generate a Poh1-dependent K63-deubiquitinating enzyme to facilitate protein aggregate clearance.
authors.affiliation: From the Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina 27710.
authors.forename: Priyaanka
authors.initials: P
authors.lastname: Nanduri
authors.affiliation: From the Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina 27710.
authors.forename: Rui
authors.initials: R
authors.lastname: Hao
authors.affiliation: From the Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina 27710.
authors.forename: Thomas
authors.initials: T
authors.lastname: Fitzpatrick
authors.affiliation: From the Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina 27710 tsopang.yao@duke.edu.
authors.forename: Tso-Pang
authors.initials: TP
authors.lastname: Yao
mesh_terms: D016227:Benzoquinones / Q000494:pharmacology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D007976:Leupeptins / Q000494:pharmacology; D008239:Lysine / Q000378:metabolism*; D018613:Microscopy, Confocal; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism*; D066329:Protein Aggregates / Q000187:drug effects; D034622:RNA Interference; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism*; D054875:Ubiquitination / Q000187:drug effects
chemical_list: D016227:Benzoquinones; D015853:Cysteine Proteinase Inhibitors; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D007976:Leupeptins; C109285:PSMD14 protein, human; D066329:Protein Aggregates; D015534:Trans-Activators; D025801:Ubiquitin; C448659:17-(dimethylaminoethylamino)-17-demethoxygeldanamycin; C108898:PSMB4 protein, human; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases; D008239:Lysine; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde
keywords: aggresome; autophagy; deubiquitylation (deubiquitination); histone deacetylase 6 (HDAC6); proteasome; ubiquitin