title: Peptides derived from the bifunctional kinase/RNase enzyme IRE1α modulate IRE1α activity and protect cells from endoplasmic reticulum stress.
abstract: Activation of the bifunctional kinase/RNase enzyme IRE1α is part of an adaptive response triggered on accumulation of misfolded proteins in the endoplasmic reticulum (ER). To facilitate recovery of ER homeostasis, IRE1α 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 IRE1α activity, we investigated IRE1α oligomerization properties using IRE1α-derived peptides identified through an activity-based in vitro assay. We then used these peptides to probe IRE1α 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 IRE1α, which promoted IRE1α oligomerization in vitro, enhanced its Xbp1 mRNA cleavage activity in vitro (1.7×) in cell culture (1.8×) and in vivo (1.3×), 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 IRE1α may consequently define new strategies to protect cells from deleterious effects of ER stress signaling.
authors.affiliation: Inserm U1053, Avenir, Université Bordeaux 2, 146 rue Léo Saignat, 33076 Bordeaux, France.
authors.forename: Marion
authors.initials: M
authors.lastname: Bouchecareilh
authors.forename: Arisa
authors.initials: A
authors.lastname: Higa
authors.forename: Sébastien
authors.initials: S
authors.lastname: Fribourg
authors.forename: Michel
authors.initials: M
authors.lastname: Moenner
authors.forename: Eric
authors.initials: E
authors.lastname: Chevet
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D004722:Endoribonucleases / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D010455:Peptides; D011487:Protein Conformation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D000071701:Regulatory Factor X Transcription Factors; D015398:Signal Transduction; D013312:Stress, Physiological; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D000071717:X-Box Binding Protein 1
chemical_list: D004268:DNA-Binding Proteins; D010455:Peptides; D012333:RNA, Messenger; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; C528229:ERN1 protein, human; D017346:Protein Serine-Threonine Kinases; D048670:MAP Kinase Kinase 4; D004722:Endoribonucleases