Precise protein folding by the endoplasmic reticulum (ER) supports homeostasis, while cumulative protein misfolding causes ER stress and promotes disease. The kinases PERK and IRE1 help orchestrate the unfolded protein response (UPR) to alleviate ER stress; however, if stress persists, the UPR activates apoptosis to eliminate the damaged cell. We have previously shown that PERK drives cell death via transcriptional up-regulation of the pro-apoptotic death receptor DR5; we further showed that IRE1—which harbors both kinase and RNase modules—blocks apoptosis through regulated IRE1-dependent mRNA decay (RIDD) of DR5 (Lu et al, Science 2014). Recently, we turned to investigate the paradoxical observation that under irresolvable ER stress PERK activity persists, while IRE1 function attenuates. We discovered that PERK governs the attenuation of IRE1, through a phosphatase called RNA polymerase II-associated protein 2 (RPAP2). RPAP2 reverses IRE1 phosphorylation, inhibiting IRE1 RNase activation. This disrupts IRE1-dependent generation of the cytoprotective transcription factor XBP1s and dampens ER-associated degradation of misfolded proteins. Furthermore, it inhibits RIDD, thereby licensing DR5-mediated caspase activation and apoptotic cell death. Thus, under excessive ER stress, PERK attenuates IRE1 via RPAP2 to abort failed adaptation and trigger an apoptotic cell fate.
