Figure 1.
Prolonged activation of IRE1 may promote apoptosis. Studies with cultured cells have identified a pro-apoptotic IRE1–TRAF2–JNK pathway that can be activated by prolonged ER stress. Signal transduction between IRE1–TRAF2 and phosphorylation of JNK may be mediated in certain settings by the MAP kinase kinase kinase (MAPKKK) ASK1 and its activator, AIP1. JNK-induced apoptosis may involve the pro-apoptotic Bcl-2 family members, Bax and Bak, which in turn, can amplify the IRE1 signal. Prolonged IRE1-mediated activation of the RIDD pathway may promote apoptosis by degrading mRNAs encoding essential cell-survival proteins, including XPB1 itself.