Convergence of orphan quality control pathways at a ubiquitin chain-elongating ligase
Unassembled and partially assembled subunits of multi-protein complexes have emerged as major quality control clients, particularly under conditions of imbalanced gene expression such as stress, aging, and aneuploidy. The factors and mechanisms that eliminate such orphan subunits to maintain protein...
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| Main Authors: | , , , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
20 February 2025
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| In: |
Molecular cell
Year: 2025, Volume: 85, Issue: 4, Pages: [1], 815-828, e1-e10 |
| ISSN: | 1097-4164 |
| DOI: | 10.1016/j.molcel.2025.01.002 |
| Online Access: | Verlag, kostenfrei, Volltext: https://doi.org/10.1016/j.molcel.2025.01.002 Verlag, kostenfrei, Volltext: https://www.sciencedirect.com/science/article/pii/S1097276525000024 
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| Author Notes: | Sara Carrillo Roas, Yuichi Yagita, Paul Murphy, Robert Kurzbauer, Tim Clausen, Eszter Zavodszky, and Ramanujan S. Hegde |
| Summary: | Unassembled and partially assembled subunits of multi-protein complexes have emerged as major quality control clients, particularly under conditions of imbalanced gene expression such as stress, aging, and aneuploidy. The factors and mechanisms that eliminate such orphan subunits to maintain protein homeostasis are incompletely defined. Here, we show that the UBR4-KCMF1 ubiquitin ligase complex is required for the efficient degradation of multiple unrelated orphan subunits from the chaperonin, proteasome cap, proteasome core, and a protein targeting complex. Epistasis analysis in cells and reconstitution studies in vitro show that the UBR4-KCMF1 complex acts downstream of a priming ubiquitin ligase that first mono-ubiquitinates orphans. UBR4 recognizes both the orphan and its mono-ubiquitin and builds a K48-linked poly-ubiquitin degradation signal. The discovery of a convergence point for multiple quality control pathways may explain why aneuploid cells are especially sensitive to loss of UBR4 or KCMF1 and identifies a potential vulnerability across many cancers. |
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| Item Description: | Online veröffentlicht: 28. Januar 2025, Artikelversion: 20. Februar 2025 Gesehen am 01.10.2025 |
| Physical Description: | Online Resource |
| ISSN: | 1097-4164 |
| DOI: | 10.1016/j.molcel.2025.01.002 |