The kinases PERK and IRE1 alleviate endoplasmic reticulum (ER) stress by orchestrating the unfolded protein response (UPR). If stress mitigation fails, PERK promotes cell death by activating pro-apoptotic genes, including death receptor 5 (DR5). Conversely, IRE1—which harbors both kinase and endoribonuclease (RNase) modules—blocks apoptosis through regulated IRE1-dependent decay (RIDD) of DR5 mRNA. Under irresolvable ER stress, PERK activity persists, whereas IRE1 paradoxically attenuates, by mechanisms that remain obscure. Here, we report that PERK governs IRE1’s attenuation through a phosphatase known as RPAP2 (RNA polymerase II-associated protein 2). RPAP2 reverses IRE1 phosphorylation, oligomerization, and RNase activation. This inhibits IRE1-mediated adaptive events, including activation of the cytoprotective transcription factor XBP1s, and ER-associated degradation of unfolded proteins. Furthermore, RIDD termination by RPAP2 unleashes DR5-mediated caspase activation and drives cell death. Thus, PERK attenuates IRE1 via RPAP2 to abort failed ER-stress adaptation and trigger apoptosis. Display omitted •PERK attenuates IRE1 during the terminal UPR via the phosphatase RPAP2•RPAP2 dephosphorylates serine residues in IRE1’s kinase-activation loop•Dephosphorylation by RPAP2 inhibits IRE1’s enoribonuclease activity•RPAP2 stops IRE1-dependent adaptation while unleashing DR5-mediated apoptosis Chang et al. shed light on the puzzle that the pivotal unfolded protein response (UPR) sensor IRE1 first activates but then attenuates, despite unresolved ER stress. Another key UPR sensor—PERK—shuts IRE1 down via the phosphatase RPAP2. IRE1 dephosphorylation aborts its adaptive functions while licensing PERK-driven apoptosis via death receptor 5.