Protein aggregation can inhibit clathrin-mediated endocytosis by chaperone competition

Anan Yu, Yoko Shibata, Bijal Shah, Barbara Calamini, Donald C. Lo, Richard I. Morimoto*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

98 Scopus citations


Protein conformational diseases exhibit complex pathologies linked to numerous molecular defects. Aggregation of a diseaseassociated 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 aggregateassociated 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.

Original languageEnglish (US)
Pages (from-to)E1481-E1490
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number15
StatePublished - Apr 15 2014


  • Chaperone-Dependent Processes
  • Hsp70
  • Protein Misfolding
  • Proteostasis

ASJC Scopus subject areas

  • General


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