Figure 3.

Downstream effects of IRE1 activation. Activation of IRE1α by dimerization and autophosphorylation leads to activities by the resulting dimer and by higher-order multimers, which are thought to have enhanced activity. Beneficial effects of IRE1 (increased folding capacity, survival and proliferation) are mostly due to RNase-induced splicing of Xbp1 to generate the sXBP1 transcription factor. RNase activity can also be harmful in the setting of unregulated degradation of ER-associated RNAs in a process called RIDD, which cleaves a number of mRNAs including some related to β-cell maturation status and cell survival. IRE1α kinase activity results in a TRAF2-ASK1-JNK kinase cascade, leading to excess cell death by multiple mechanisms. Green arrows indicate transcriptional regulation. ASK1, apoptosis signal regulating kinase 1; CHOP, C/EBP homologous protein; DP5, death domain protein 5; IRE1, inositol-requiring enzyme 1; JNK, c-Jun N-terminal kinase; circled P indicates phosphorylation; TRAF2, TNF receptor–associated factor 2; Xbp1, X-box binding protein 1; uXbp1, unspliced Xbp1; sXbp1, spliced Xbp1.