Transmembrane E3 ligase RNF183 mediates ER stress-induced apoptosis by degrading Bcl-xL

Significance The accumulation of unfolded proteins in the endoplasmic reticulum (ER) is a pathological condition observed in many diseases, including cancer, diabetes, and neurodegenerative diseases. Failure to relieve the cellular stress via adaptive mechanisms of the unfolded protein response (UPR) activates apoptotic cell death. We demonstrate that a membrane-anchored RING finger protein, RNF183, is specifically induced by prolonged ER stress. RNF183 is regulated by IRE1, mainly through miR-7. As an E3 ligase, RNF183 ubiquitinates Bcl-xL, causing its degradation and subsequent apoptosis. Our findings imply that manipulation of RNF183 activity may help control cell fate in pathological conditions and suggest that the close contact between the ER and mitochondria plays a key role in cellular signaling.