ATP-competitive partial antagonists of the IRE1α RNase segregate outputs of the UPR.

Abstract

The unfolded protein response (UPR) homeostatically matches endoplasmic reticulum (ER) protein-folding capacity to cellular secretory needs. But under high/chronic ER stress, the UPR triggers apoptosis. This dichotomy is promoted by differential activation of the ER transmembrane kinase/endoribonuclease (RNase) IRE1α. We previously found that IRE1α’s RNase can be either fully activated or inactivated by ATP-competitive kinase inhibitors. Here we developed kinase inhibitors—’PAIR’s—Partial Antagonists of IRE1α RNase—that partially antagonize IRE1α’s RNase at full occupancy. Biochemical and structural studies show that PAIRs promote partial RNase antagonism by intermediately displacing the αC helix in IRE1α’s kinase domain. In insulin-producing β-cells, PAIRs permit adaptive XBP1 mRNA splicing, while quelling destructive ER mRNA endonucleolytic decay and apoptosis. By preserving XBP1 mRNA splicing, PAIRs allow B-lymphocytes to differentiate into immunoglobulin-producing plasma cells. Thus, an intermediate RNase-inhibitory “sweet spot”, achieved by PAIR-bound IRE1α captures a desirable conformation for drugging this master UPR sensor/effector.