title: Proteasomes activate aggresome disassembly and clearance by producing unanchored ubiquitin chains.
abstract: Aberrant protein aggregation is a dominant pathological feature in neurodegenerative diseases. Protein aggregates cannot be processed by the proteasome; instead, they are frequently concentrated to the aggresome, a perinuclear inclusion body, and subsequently removed by autophagy. Paradoxically, proteasomes are also concentrated at aggresomes and other related inclusion bodies prevalent in neurodegenerative disease. Here, we show that proteasomes are crucial components in aggresome clearance. The disassembly and disposal of aggresomes requires Poh1, a proteasomal deubiquitinating enzyme that cleaves ubiquitinated proteins and releases ubiquitin chains. In Poh1-deficient cells, aggresome clearance is blocked. Remarkably, microinjection of free lysine (K) 63-linked ubiquitin chains restores aggresome degradation. We present evidence that free ubiquitin chains produced by Poh1 bind and activate the deacetylase HDAC6, which, in turn, stimulates actinomyosin- and autophagy-dependent aggresome processing. Thus, unanchored ubiquitin chains are key signaling molecules that connect and coordinate the proteasome and autophagy to eliminate toxic protein aggregates.
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA.
authors.forename: Rui
authors.initials: R
authors.lastname: Hao
authors.forename: Priyaanka
authors.initials: P
authors.lastname: Nanduri
authors.forename: Yanhua
authors.initials: Y
authors.lastname: Rao
authors.forename: R Scott
authors.initials: RS
authors.lastname: Panichelli
authors.forename: Akihiro
authors.initials: A
authors.lastname: Ito
authors.forename: Minoru
authors.initials: M
authors.lastname: Yoshida
authors.forename: Tso-Pang
authors.initials: TP
authors.lastname: Yao
mesh_terms: D001343:Autophagy; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D002479:Inclusion Bodies / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism*; D017510:Protein Folding; D059748:Proteolysis; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
chemical_list: D025801:Ubiquitin; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex; D006655:Histone Deacetylases
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