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 the adaptive mechanisms of the unfolded protein response (UPR) activates apoptotic cell death. Prevention of unwanted apoptosis induced by prolonged ER stress is considered a valuable therapeutic strategy.

However, the mechanism of apoptotic initiation and execution in sustained ER stress is unclear. The complication of UPR signaling suggests that unknown pathways have yet to be discovered.

The researchers at Institute of Biophysics of Chinese Academy of Sciences recently identified a novel membrane-anchored RING finger protein, RNF183. It is specifically induced by prolonged ER stress, ubiquitinates Bcl-xL and causes its degradation and subsequent apoptosis. The study was published in PNAS.

They found that RNF183 localizes to the ER and its cytosolic RING finger possesses E3 ligase activity. The induction of RNF183 is controlled by IRE1, not the PERK pathway, and involves miR7. Besides, they reveal that RNF183 interacts with anti-apoptotic factor Bcl-xL, ubiquitinates the protein and causing its degradation and subsequent apoptosis. Depletion of RNF183 preserves the levels of Bcl-xL and alleviates apoptosis triggered by prolonged ER stress.

These findings implied that manipulation of RNF183 activity may help control cell fate in pathological conditions, and suggested that the close contact between the ER and mitochondria play a key role in cellular signaling.

This work was supported by the National Key Research and Development Program and the National Natural Science Foundation of China.

A model for RNF183-induced apoptosis during prolonged ER stress (Image by HU Junjie)