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Protein aggregation can inhibit clathrin-mediated endocytosis by chaperone competition.
Yu, Anan; Shibata, Yoko; Shah, Bijal; Calamini, Barbara; Lo, Donald C; Morimoto, Richard I.
Affiliation
  • Yu A; Department of Molecular Biosciences, Rice Institute for Biomedical Research, Northwestern University, Evanston, IL 60208.
Proc Natl Acad Sci U S A ; 111(15): E1481-90, 2014 Apr 15.
Article in En | MEDLINE | ID: mdl-24706768
Protein conformational diseases exhibit complex pathologies linked to numerous molecular defects. Aggregation of a disease-associated protein causes the misfolding and aggregation of other proteins, but how this interferes with diverse cellular pathways is unclear. Here, we show that aggregation of neurodegenerative disease-related proteins (polyglutamine, huntingtin, ataxin-1, and superoxide dismutase-1) inhibits clathrin-mediated endocytosis (CME) in mammalian cells by aggregate-driven sequestration of the major molecular chaperone heat shock cognate protein 70 (HSC70), which is required to drive multiple steps of CME. CME suppression was also phenocopied by HSC70 RNAi depletion and could be restored by conditionally increasing HSC70 abundance. Aggregation caused dysregulated AMPA receptor internalization and also inhibited CME in primary neurons expressing mutant huntingtin, showing direct relevance of our findings to the pathology in neurodegenerative diseases. We propose that aggregate-associated chaperone competition leads to both gain-of-function and loss-of-function phenotypes as chaperones become functionally depleted from multiple clients, leading to the decline of multiple cellular processes. The inherent properties of chaperones place them at risk, contributing to the complex pathologies of protein conformational diseases.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Protein Conformation / Proteins / Clathrin / Molecular Chaperones / Endocytosis / Neurons Limits: Animals Language: En Journal: Proc Natl Acad Sci U S A Year: 2014 Document type: Article Country of publication: United States

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Protein Conformation / Proteins / Clathrin / Molecular Chaperones / Endocytosis / Neurons Limits: Animals Language: En Journal: Proc Natl Acad Sci U S A Year: 2014 Document type: Article Country of publication: United States