Proteasomes activate aggresome disassembly and clearance by producing unanchored ubiquitin chains.

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Hao, R; Nanduri, P; Rao, Y; Panichelli, RS; Ito, A; Yoshida, M; Yao, T-P

Published Date

  • September 26, 2013

Published In

Volume / Issue

  • 51 / 6

Start / End Page

  • 819 - 828

PubMed ID

  • 24035499

Pubmed Central ID

  • PMC3791850

Electronic International Standard Serial Number (EISSN)

  • 1097-4164

Digital Object Identifier (DOI)

  • 10.1016/j.molcel.2013.08.016


  • eng

Conference Location

  • United States