ArticleMolecular biology of the cell2013
Ubiquitin conjugation triggers misfolded protein sequestration into quality control foci when Hsp70 chaperone levels are limiting.
Article in Molecular biology of the cell, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 72 papers.
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Who cites it
72 citing papers in PubMed, 111 citations in OpenAlex.
- FBXL21 regulates diurnal proteostasis in skeletal muscle by targeting DNAJB6 and client proteins.EMBO reports · 2026Article
- Tyrosine Supplementation Rescues a Growth Defect in a HumanizedInternational journal of molecular sciences · 2026Article
- Inhibition of the integrated stress response rescues a histidyl-tRNA synthetase variant associated with Charcot-Marie-Tooth disease.NAR molecular medicine · 2026Article
- Stress-inducible phosphoprotein 1 (Sti1/Stip1/Hop) sequesters misfolded proteins during stress.The FEBS journal · 2025Article
- Hsp70 chaperones, Ssa1 and Ssa2, limit poly(A) binding protein aggregation.Molecular biology of the cell · 2025Article
- A novel peptide encoded by circSRCAP confers resistance to enzalutamide by inhibiting the ubiquitin-dependent degradation of AR-V7 in castration-resistant prostate cancer.Journal of translational medicine · 2025Article
- Transfer RNA supplementation rescues HARS deficiency in a humanized yeast model of Charcot-Marie-Tooth disease.Nucleic acids research · 2024Article
- Characterization of a novel heterozygous variant in the histidyl-tRNA synthetase gene associated with Charcot-Marie-Tooth disease type 2W.IUBMB life · 2024Article
- Elucidation of Site-Specific Ubiquitination on Chaperones in Response to Mutant Huntingtin.Cellular and molecular neurobiology · 2023Article
- Review
- International Union of Basic and Clinical Pharmacology CXIII: Nuclear Receptor Superfamily-Update 2023.Pharmacological reviews · 2023Review
- Mechanisms of substrate processing during ER-associated protein degradation.Nature reviews. Molecular cell biology · 2023Review
- Mechanisms of genotoxicity and proteotoxicity induced by the metalloids arsenic and antimony.Cellular and molecular life sciences : CMLS · 2023Review
- Fusion of Hsp70 to GFP Impairs Its Function and Causes Formation of Misfolded Protein Deposits under Mild Stress in Yeast.International journal of molecular sciences · 2023Article
- The GET pathway is a major bottleneck for maintaining proteostasis in Saccharomyces cerevisiae.Scientific reports · 2023Article
- Artificial Hsp104-mediated systems for re-localizing protein aggregates.Nature communications · 2023Article
- Histidine supplementation can escalate or rescue HARS deficiency in a Charcot-Marie-Tooth disease model.Human molecular genetics · 2023Article
- HSP70-binding motifs function as protein quality control degrons.Cellular and molecular life sciences : CMLS · 2023Article
- Inactive Proteasomes Routed to Autophagic Turnover Are Confined within the Soluble Fraction of the Cell.Biomolecules · 2022Article
- Yeast polyubiquitin unit regulates synaptonemal complex formation and recombination during meiosis.Journal of microbiology (Seoul, Korea) · 2022Article
12 more citing papers are in PubMed but not listed here.
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Authors and funding
4 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Ubiquitin accumulation in amyloid plaques is a pathological marker observed in the vast majority of neurodegenerative diseases, yet ubiquitin function in these inclusions is controversial. It has been suggested that ubiquitylated proteins are directed to inclusion bodies under stress conditions, when both chaperone-mediated refolding and proteasomal degradation are compromised or overwhelmed. Alternatively, ubiquitin and chaperones may be recruited to preformed inclusions to promote their elimination. We address this issue using a yeast model system, based on expression of several mildly misfolded degradation substrates in cells with altered chaperone content. We find that the heat shock protein 70 (Hsp70) chaperone pair Ssa1/Ssa2 and the Hsp40 cochaperone Sis1 are essential for degradation. Substrate ubiquitylation is strictly dependent on Sis1, whereas Ssa1 and Ssa2 are dispensable. Remarkably, in Ssa1/Ssa2-depleted cells, ubiquitylated substrates are sequestered into detergent-insoluble, Hsp42-positive inclusion bodies. Unexpectedly, sequestration is abolished by preventing substrate ubiquitylation. We conclude that Hsp40 is required for the targeting of misfolded proteins to the ubiquitylation machinery, whereas the decision to degrade or sequester ubiquitylated proteins is mediated by the Hsp70s. Accordingly, diminished Hsp70 levels, as observed in aging or certain pathological conditions, might be sufficient to trigger ubiquitin-dependent sequestration of partially misfolded proteins into inclusion bodies.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.