ArticleThe EMBO journal2013
Why do cellular proteins linked to K63-polyubiquitin chains not associate with proteasomes?
Article in The EMBO journal, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 166 papers.
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Who cites it
166 citing papers in PubMed, 255 citations in OpenAlex.
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- ETV4 promotes ovarian cancer growth by regulating mitochondrial function through Mfn2 ubiquitination mediated by the E3 ubiquitin ligase MARCH9.Cell biology and toxicology · 2025Article
- Ubiquitin chain variability directs substrates of the Tul1 ubiquitin ligase complex to different degradation pathways.The Journal of cell biology · 2025Article
- The WWP1-JARID1B axis sustains acute myeloid leukemia chemoresistance.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Cypin regulates K63-linked polyubiquitination to shape synaptic content.Science advances · 2025Article
- AKT and DUBs: a bidirectional relationship.Cellular & molecular biology letters · 2025Review
- Lysosomal quality control Review.Autophagy · 2025Review
- Covalent inhibition ofiScience · 2025Article
- α-Synuclein Pathology in Synucleinopathies: Mechanisms, Biomarkers, and Therapeutic Challenges.International journal of molecular sciences · 2025Review
- The Lysine Deprotonation Mechanism in a Ubiquitin Conjugating Enzyme.The journal of physical chemistry. B · 2025Article
- Cd stabilizes HIF-1α under normoxic conditions via lysine-63-linked ubiquitination and induces ER stress and cell proliferation.Toxicological research · 2025Article
- SOD2 is a regulator of proteasomal degradation promoting an adaptive cellular starvation response.Cell reports · 2025Article
- Trafficking of K63-polyubiquitin-modified membrane proteins in a macroautophagy-independent pathway is linked to ATG9A.Molecular biology of the cell · 2025Article
- The adaptor protein AP-3β disassembles heat-induced stress granules via 19S regulatory particle in Arabidopsis.Nature communications · 2025Article
- OTUD5 Protects Dopaminergic Neurons by Promoting the Degradation of α-Synuclein in Parkinson's Disease Model.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
106 more citing papers are in PubMed but not listed here.
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Authors and funding
5 authors at 1 institution in 2 countries.
Funding
Abstract
Although cellular proteins conjugated to K48-linked Ub chains are targeted to proteasomes, proteins conjugated to K63-ubiquitin chains are directed to lysosomes. However, pure 26S proteasomes bind and degrade K48- and K63-ubiquitinated substrates similarly. Therefore, we investigated why K63-ubiquitinated proteins are not degraded by proteasomes. We show that mammalian cells contain soluble factors that selectively bind to K63 chains and inhibit or prevent their association with proteasomes. Using ubiquitinated proteins as affinity ligands, we found that the main cellular proteins that associate selectively with K63 chains and block their binding to proteasomes are ESCRT0 (Endosomal Sorting Complex Required for Transport) and its components, STAM and Hrs. In vivo, knockdown of ESCRT0 confirmed that it is required to block binding of K63-ubiquitinated molecules to the proteasome. In addition, the Rad23 proteins, especially hHR23B, were found to bind specifically to K48-ubiquitinated proteins and to stimulate proteasome binding. The specificities of these proteins for K48- or K63-ubiquitin chains determine whether a ubiquitinated protein is targeted for proteasomal degradation or delivered instead to the endosomal-lysosomal pathway.
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Registered trials
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.