title: A combined "omics" approach identifies N-Myc interactor as a novel cytokine-induced regulator of IRE1 protein and c-Jun N-terminal kinase in pancreatic beta cells.
abstract: Type 1 diabetes is an autoimmune disease with a strong inflammatory component. The cytokines interleukin-1β and interferon-γ contribute to beta cell apoptosis in type 1 diabetes. These cytokines induce endoplasmic reticulum stress and the unfolded protein response (UPR), contributing to the loss of beta cells. IRE1α, one of the UPR mediators, triggers insulin degradation and inflammation in beta cells and is critical for the transition from "physiological" to "pathological" UPR. The mechanisms regulating inositol-requiring protein 1α (IRE1α) activation and its signaling for beta cell "adaptation," "stress response," or "apoptosis" remain to be clarified. To address these questions, we combined mammalian protein-protein interaction trap-based IRE1α interactome and functional genomic analysis of human and rodent beta cells exposed to pro-inflammatory cytokines to identify novel cytokine-induced regulators of IRE1α. Based on this approach, we identified N-Myc interactor (NMI) as an IRE1α-interacting/modulator protein in rodent and human pancreatic beta cells. An increased expression of NMI was detected in islets from nonobese diabetic mice with insulitis and in rodent or human beta cells exposed in vitro to the pro-inflammatory cytokines interleukin-1β and interferon-γ. Detailed mechanistic studies demonstrated that NMI negatively modulates IRE1α-dependent activation of JNK and apoptosis in rodent and human pancreatic beta cells. In conclusion, by using a combined omics approach, we identified NMI induction as a novel negative feedback mechanism that decreases IRE1α-dependent activation of JNK and apoptosis in cytokine-exposed beta cells
authors.forename: Flora
authors.initials: F
authors.lastname: Brozzi
authors.forename: Sarah
authors.initials: S
authors.lastname: Gerlo
authors.forename: Fabio Arturo
authors.initials: FA
authors.lastname: Grieco
authors.forename: Tarlliza Romanna
authors.initials: TR
authors.lastname: Nardelli
authors.forename: Sam
authors.initials: S
authors.lastname: Lievens
authors.forename: Conny
authors.initials: C
authors.lastname: Gysemans
authors.forename: Lorella
authors.initials: L
authors.lastname: Marselli
authors.forename: Piero
authors.initials: P
authors.lastname: Marchetti
authors.forename: Chantal
authors.initials: C
authors.lastname: Mathieu
authors.forename: Jan
authors.initials: J
authors.lastname: Tavernier
authors.forename: Décio L
authors.initials: DL
authors.lastname: Eizirik
mesh_terms: D000368:Aged; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D004722:Endoribonucleases / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism*; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism*; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008875:Middle Aged; D009097:Multienzyme Complexes / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D056811:Unfolded Protein Response / Q000502:physiology*
chemical_list: C575026:Ern1 protein, rat; C573415:IFNG protein, human; C508585:IL1B protein, human; C000594089:IL1B protein, rat; D053583:Interleukin-1beta; D047908:Intracellular Signaling Peptides and Proteins; D009097:Multienzyme Complexes; C099927:NMI protein, human; D007371:Interferon-gamma; C528229:ERN1 protein, human; D017346:Protein Serine-Threonine Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D004722:Endoribonucleases