A Tale of Two Distinct Mechanisms for IRE1 RNase (752.9)

IRE1, an ER transmembrane receptor kinase, is a component of the Unfolded Protein Response (UPR) pathway, and acts as an endoribonuclease (RNase) to cleave the intron from XBP1/HAC1 mRNA coding an UPR‐specific transcription factor. Interestingly, recent reports have revealed that UPR also induces a decrease in levels of ER‐associated mRNAs, including INSULIN mRNA in an IRE1‐dependent manner1, which has been termed Regulated IRE1 Dependent Decay (RIDD). While XBP1/HAC1 splicing and RIDD are proposed to be carried out by IRE1, the mechanism by which IRE1 differentiates between XBP1/HAC1 and RIDD substrate mRNAs has not been investigated. Major differences in the cleavage of the HAC1/XBP1 intron and of RIDD RNA include RNA sequences at the cleavage sites, and that HAC1/XBP1 mRNA cleavage occurs at the ends of the intron whereas certain RIDD substrate RNA are cleaved at multiple sites. In addition, HAC1/XBP1 exon cleavage must be coordinated with tRNA ligase activity while RIDD RNA fragments should be shielded from tRNA ligase to promote their degradation.