期刊
DEVELOPMENTAL CELL
卷 44, 期 6, 页码 694-+出版社
CELL PRESS
DOI: 10.1016/j.devcel.2018.02.001
关键词
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资金
- JSPS KAKENHI [JP25893275, 15H05643, 15H01192]
- Mitsubishi Foundation
- Uehara Memorial Foundation
- Sumitomo Foundation
- Mochida Memorial Foundation for Medical and Pharmaceutical Research
- Astellas Foundation for Research on Metabolic Disorders
- NIH-NIDDK [DK075302]
- CIHR
- Cystic Fibrosis Canada
- Grants-in-Aid for Scientific Research [15H01192, 15H05643] Funding Source: KAKEN
The peripheral protein quality control (QC) system removes non-native membrane proteins, including Delta F508-CFTR, the most common CFTR mutant in cystic fibrosis (CF), from the plasma membrane (PM) for lysosomal degradation by ubiquitination. It remains unclear how unfolded membrane proteins are recognized and targeted for ubiquitination and how they are removed from the apical PM. Using comprehensive siRNA screens, we identified RFFL, an E3 ubiquitin (Ub) ligase that directly and selectively recognizes unfolded Delta F508-CFTR through its disordered regions. RFFL retrieves the unfolded CFTR from the PM for lysosomal degradation by chaperone-independent K63-linked poly-ubiquitination. RFFL ablation enhanced the functional expression of cell-surface Delta F508-CFTR in the presence of folding corrector molecules, and this effect was further improved by inhibiting the Hsc70-dependent ubiquitination machinery. We propose that multiple peripheral QC mechanisms evolved to dispose of non-native PM proteins and to preserve cellular proteostasis, even at the cost of eliminating partially functional polypeptides.
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