期刊
EMBO REPORTS
卷 17, 期 6, 页码 842-857出版社
WILEY
DOI: 10.15252/embr.201541402
关键词
BAG6; proteasome; signal sequence; SRP; ubiquitin
资金
- Ministry of Education, Culture, Science, and Technology of Japan (Ubiquitin neo-biology) [24112007]
- Uehara Memorial Foundation
- Naito Foundation
- JSPS Research Fellowship for Young Scientists [265957]
- Grants-in-Aid for Scientific Research [14J05957, 24112007] Funding Source: KAKEN
The majority of transmembrane proteins are integrated into the endoplasmic reticulum (ER) by virtue of a signal sequence-mediated co-translational process. However, a substantial portion of transmembrane proteins fails to reach the ER, leading to mis-localized cytosolic polypeptides. Their appropriate recognition and removal are of the utmost importance to avoid proteotoxic stress. Here, we identified UBQLN4 as a BAG6-binding factor that eliminates newly synthesized defective polypeptides. Using a truncated transmembrane domain protein whose degradation occurs during a pre-ER incorporation process as a model, we show that UBQLN4 recognizes misassembled proteins in the cytoplasm and targets these to the proteasome. We suggest that the exposed transmembrane segment of the defective polypeptides is essential for the UBQLN4-mediated substrate discrimination. Importantly, UBQLN4 recognizes not only the defective model substrate but also a pool of endogenous defective proteins that were induced by the depletion of the SRP54 subunit of the signal recognition particle. This study identifies a novel quality control mechanism for newly synthesized and defective transmembrane domain polypeptides that fail to reach their correct destination at the ER membrane.
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