ArticleProceedings of the National Academy of Sciences of the United States of America2014
Protein aggregation can inhibit clathrin-mediated endocytosis by chaperone competition.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 86 papers.
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Who cites it
86 citing papers in PubMed.
- Differential proteostasis imbalance and the molecular basis of distinct synucleinopathies and tauopathies.Philosophical transactions of the Royal Society of London. Series B, Biological sciences · 2026Review
- Synaptic Chaperone Dysfunction as a Convergent Mechanism in Neurodegenerative and Psychiatric Disorders.Neuroscience insights · 2026Review
- Heat shock proteins at the crossroads of endosomal trafficking pathways.Cell biology and toxicology · 2025Review
- Stress granules and protein aggregates reveal intracellular resource competition.bioRxiv : the preprint server for biology · 2025Article
- Proteostasis and Its Role in Disease Development.Cell biochemistry and biophysics · 2025Review
- Increased Activity-Dependent Bulk Endocytosis in Huntington's Disease Results From Huntingtin Haploinsufficiency.Journal of neurochemistry · 2025Article
- Ubiquitin-Proteasome System Dysregulation in Alzheimer's Disease Impacts Protein Abundance.bioRxiv : the preprint server for biology · 2025Article
- Proteostasis and metabolic dysfunction characterize a subset of storage-induced senescent erythrocytes targeted for posttransfusion clearance.The Journal of clinical investigation · 2025Article
- Endocytic Pathways Unveil the Role of Syndecans in the Seeding and Spreading of Pathological Protein Aggregates: Insights into Neurodegenerative Disorders.International journal of molecular sciences · 2025Review
- Article
- The mechanism of mitochondrial autophagy regulating Clathrin-mediated endocytosis in epilepsy.Epilepsia open · 2024Article
- Tau fibrils evade autophagy by excessive p62 coating and TAX1BP1 exclusion.Science advances · 2024Article
- Mutant huntingtin confers cell-autonomous phenotypes on Huntington's disease iPSC-derived microglia.Scientific reports · 2023Article
- Cellular Exposure to Chloroacetanilide Herbicides Induces Distinct Protein Destabilization Profiles.ACS chemical biology · 2023Article
- Regulation of germline proteostasis by HSF1 and insulin/IGF-1 signaling.Biochemical Society transactions · 2023Article
- Genetic background influences pig responses to porcine reproductive and respiratory syndrome virus.Frontiers in veterinary science · 2023Review
- Reversible protein assemblies in the proteostasis network in health and disease.Frontiers in molecular biosciences · 2023Review
- Reduced endosomal microautophagy activity in aging associates with enhanced exocyst-mediated protein secretion.Aging cell · 2022Article
- Heat Shock Protein Member 8 (HSPA8) Is Involved in Porcine Reproductive and Respiratory Syndrome Virus Attachment and Internalization.Microbiology spectrum · 2022Article
- Review
26 more citing papers are in PubMed but not listed here.
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Authors and funding
6 authors.
Funding
Abstract
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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