Peptides derived from the bifunctional kinase/RNase enzyme IRE1α modulate IRE1α activity and protect cells from endoplasmic reticulum stress

Activation of the bifunctional kinase/RNase enzyme IRE1 alpha is part of an adaptive response triggered on accumulation of misfolded proteins in the endoplasmic reticulum (ER). To facilitate recovery of ER homeostasis, IRE1 alpha molecules oligomerize, allowing for their transautophosphorylation and endoribonuclease activation. These, in turn, induce the activation of specific transcriptional and post-transcriptional programs. To identify novel and selective modulators of IRE1 alpha activity, we investigated IRE1 alpha oligomerization properties using IRE1 alpha-derived peptides identified through an activity-based in vitro assay. We then used these peptides to probe IRE1 alpha activity in vitro and in vivo using both cultured human hepatocellular carcinoma-derived HuH7 cells and Caenorhabditis elegans experimental systems. We identified a peptide derived from the kinase domain of human IRE1 alpha, which promoted IRE1 alpha oligomerization in vitro, enhanced its Xbp1 mRNA cleavage activity in vitro (1.7 x) in cell culture (1.8 x) and in vivo (1.3 x), and attenuated both ER stress-mediated JNK activation and regulated IRE1-dependent mRNA decay (RIDD). This was accompanied by a 2.5-fold increase in survival on tunicamycin-induced ER stress and reduced apoptosis by 1.4-fold in cells expressing this peptide. Hence, targeted and selective activation of the catalytic properties of IRE1 alpha may consequently define new strategies to protect cells from deleterious effects of ER stress signaling.-Bouchecareilh, M., Higa, A., Fribourg, S., Moenner, M., Chevet, E. Peptides derived from the bifunctional kinase/RNase enzyme IRE1 alpha modulate IRE1 alpha activity and protect cells from endoplasmic reticulum stress. FASEB J. 25, 3115-3129 (2011). www.fasebj.org