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J Cell Biol. 2016 Apr 25;213(2):229-41. doi: 10.1083/jcb.201511024.

Protein misfolding specifies recruitment to cytoplasmic inclusion bodies.

Author information

1
Department of Biology, Stanford University, Stanford, CA 94305.
2
Department of Genetics, The Hebrew University of Jerusalem, Jerusalem 91904, Israel.
3
Department of Biology, Stanford University, Stanford, CA 94305 kopito@stanford.edu.

Abstract

Inclusion bodies (IBs) containing aggregated disease-associated proteins and polyubiquitin (poly-Ub) conjugates are universal histopathological features of neurodegenerative diseases. Ub has been proposed to target proteins to IBs for degradation via autophagy, but the mechanisms that govern recruitment of ubiquitylated proteins to IBs are not well understood. In this paper, we use conditionally destabilized reporters that undergo misfolding and ubiquitylation upon removal of a stabilizing ligand to examine the role of Ub conjugation in targeting proteins to IBs that are composed of an N-terminal fragment of mutant huntingtin, the causative protein of Huntington's disease. We show that reporters are excluded from IBs in the presence of the stabilizing ligand but are recruited to IBs after ligand washout. However, we find that Ub conjugation is not necessary to target reporters to IBs. We also report that forced Ub conjugation by the Ub fusion degradation pathway is not sufficient for recruitment to IBs. Finally, we find that reporters and Ub conjugates are stable at IBs. These data indicate that compromised folding states, rather than conjugation to Ub, can specify recruitment to IBs.

PMID:
27114501
PMCID:
PMC5084276
DOI:
10.1083/jcb.201511024
[Indexed for MEDLINE]
Free PMC Article

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