RNase domains determine the functional difference between IRE1alpha and IRE1beta.

Endoplasmic reticulum (ER) stress is associated with the functional disorder of the ER. During conditions of ER stress, cells induce at least two responses to maintain ER function: transcriptional upregulation of ER quality control genes, and translational attenuation of protein synthesis. Induction of ER quality control proteins is mediated by IRE1alpha, which activates the transcription factor XBP1 via an unconventional splicing event, while a partial translational attenuation is mediated by IRE1beta. Here, we show by both in vivo and in vitro analyses that the RNase domain of IRE1 determines the functional specificities of each of these isoforms.