Discovery of\na Compound That Inhibits IRE1α <i>S</i>‑Nitrosylation\nand Preserves the Endoplasmic Reticulum\nStress Response under Nitrosative Stress

Inositol-requiring enzyme 1α (IRE1α) is a\nsensor of\nendoplasmic reticulum (ER) stress and drives ER stress response pathways.\nActivated IRE1α exhibits RNase activity and cleaves mRNA encoding\nX-box binding protein 1, a transcription factor that induces the expression\nof genes that maintain ER proteostasis for cell survival. Previously,\nwe showed that IRE1α undergoes <i>S</i>-nitrosylation,\na post-translational modification induced by nitric oxide (NO), resulting\nin reduced RNase activity. Therefore, <i>S</i>-nitrosylation\nof IRE1α compromises the response to ER stress, making cells\nmore vulnerable. We conducted virtual screening and cell-based validation\nexperiments to identify compounds that inhibit the <i>S</i>-nitrosylation of IRE1α by targeting nitrosylated cysteine\nresidues. We ultimately identified a compound (1ACTA) that selectively\ninhibits the <i>S</i>-nitrosylation of IRE1α and prevents\nthe NO-induced reduction of RNase activity. Furthermore, 1ACTA reduces\nthe rate of NO-induced cell death. Our research identified <i>S</i>-nitrosylation as a novel target for drug development for\nIRE1α and provides a suitable screening strategy.