期刊
MOLECULAR CELL
卷 63, 期 1, 页码 21-33出版社
CELL PRESS
DOI: 10.1016/j.molcel.2016.05.020
关键词
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资金
- UK Medical Research Council [MC_UP_A022_1007]
- Japan Society for the Promotion of Science
- MRC Career Development Fellowship
- MRC Postdoctoral Fellowship
- St. John's College Title A fellowship
- Medical Research Council [MC_UP_A022_1007] Funding Source: researchfish
- Grants-in-Aid for Scientific Research [16H01194, 16H06167] Funding Source: KAKEN
- MRC [MC_UP_A022_1007] Funding Source: UKRI
We investigated how mitochondrial membrane proteins remain soluble in the cytosol until their delivery to mitochondria or degradation at the proteasome. We show that Ubiquilin family proteins bind transmembrane domains in the cytosol to prevent aggregation and temporarily allow opportunities for membrane targeting. Over time, Ubiquilins recruit an E3 ligase to ubiquitinate bound clients. The attached ubiquitin engages Ubiquilin's UBA domain, normally bound to an intramolecular UBL domain, and stabilizes the Ubiquilin-client complex. This conformational change precludes additional chances at membrane targeting for the client, while simultaneously freeing Ubiquilin's UBL domain for targeting to the proteasome. Loss of Ubiquilins by genetic ablation or sequestration in polyglutamine aggregates leads to accumulation of non-inserted mitochondrial membrane protein precursors. These findings define Ubiquilins as a family of chaperones for cytosolically exposed transmembrane domains and explain how they use ubiquitin to triage clients for degradation via coordinated intra-and intermolecular interactions.
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