Ubiquilins Chaperone and Triage Mitochondrial Membrane Proteins for Degradation.
Ubiquilins Chaperone and Triage Mitochondrial Membrane Proteins for Degradation.
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DOI：
10.1016/j.molcel.2016.05.020
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发表时间：
2016-07-07
期刊：
影响因子：
16
通讯作者：
Hegde RS
中科院分区：
文献类型：
--
作者：
Itakura E;Zavodszky E;Shao S;Wohlever ML;Keenan RJ;Hegde RS
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. Ubiquilins are conserved cytosolic chaperones for transmembrane domains Mitochondrial membrane proteins that fail targeting are degraded by Ubiquilins The absence of Ubiquilins in cells leads to membrane protein precursor aggregation Interactions with Ubiquilins’ UBA and UBL domains coordinate client degradation Membrane proteins require targeting to an intracellular organelle for insertion. When targeting fails, they must be recognized and degraded promptly to avoid aggregation. Itakura et al. show that Ubiquilins are cytosolic chaperones that prevent aggregation of mitochondrial membrane protein precursors, routing them for degradation if they linger uninserted in the cytosol.
