Proteasomes Activate Aggresome Disassembly and Clearance by Producing Unanchored Ubiquitin Chains
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, pro...
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Veröffentlicht in: | Molecular cell 2013-09, Vol.51 (6), p.819-828 |
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Sprache: | eng |
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Zusammenfassung: | 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.
•Proteasomes activate aggresome clearance by producing free ubiquitin chains•Proteasomal Poh1 produces free ubiquitin chains that bind and activate HDAC6•HDAC6 activates an actinomyosin system that facilitates aggresome clearance•Free ubiquitin chains functionally connect the proteasome and autophagy |
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ISSN: | 1097-2765 1097-4164 |
DOI: | 10.1016/j.molcel.2013.08.016 |