Abstract
The accumulation of misfolded proteins in the endoplasmic reticulum (ER) causes ER stress and triggers the unfolded protein response (UPR). Failure to resolve ER stress leads to apoptotic cell death via a yet unclear mechanism. Here, we show that RNF183, a membrane-spanning RING finger protein, localizes to the ER and exhibits classic E3 ligase activities. Sustained ER stress induced by different treatments increases RNF183 protein levels posttranscriptionally in an IRE1α-dependent manner. Activated IRE1 reduces the level of miR-7, which increases the stability of RNF183 transcripts. In addition, overexpression of RNF183 leads to increased apoptosis and its depletion alleviates ER stress-induced apoptosis. Furthermore, RNF183 interacts with Bcl-xL, an antiapoptotic member of the Bcl-2 family, and polyubiquitinates Bcl-xL for degradation. Thus, RNF183 plays an important role in executing programmed cell death upon prolonged ER stress, likely by inducing apoptosis through Bcl-xL.