IRE1α is the more ancient of the two UPR sensors, and in addition to its kinase catalytic activity it contains an endoribonuclease (RNase) at its C-terminal end (Wang et al., 1998). For IRE1α, trans-autophosphorylation is a potentiating step that activates its RNase to initiate splicing of the mRNA encoding the XBP1 transcription factor. IRE1α-mediated splicing of XBP1 mRNA removes a 26 nucleotide intron, and alters the open reading frame (ORF); translated in the alternate ORF, spliced XBP1 mRNA encodes the XBP1s (s=spliced) transcription factor whose target genes enhance ER protein folding capacity (Figure S2B) (Calfon et al., 2002; Lee et al., 2003; Yoshida et al., 2001). Thus, by splicing XBP1 mRNA, IRE1α’s RNase promotes adaptation to ER stress. However, under irremediable ER stress, IRE1α’s RNase becomes hyperactive, and causes massive endonucleolytic degradation of ER-localized mRNAs and downstream c-Jun N-terminal kinase (JNK) phosphorylation to promote apoptosis (Han et al., 2009). Therefore, we decided to study if IRE1α uses TXNIP as an intermediary to trigger cell death under irremediable ER stress.
