NDLI: A Combined “Omics” Approach Identifies N-Myc Interactor as a Novel Cytokine-induced Regulator of IRE1α Protein and c-Jun N-terminal Kinase in Pancreatic Beta Cells

Content Provider	Journal of Biological Chemistry (JBC)
Author	Brozzi, Flora Gerlo, Sarah Grieco, Fabio Arturo Nardelli, Tarlliza Romanna Lievens, Sam Gysemans, Conny Marselli, Lorella Marchetti, Piero Mathieu, Chantal Tavernier, Jan Eizirik, Décio L.
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.
Related Links	http://www.jbc.org/content/289/30/20677.abstract
Ending Page	20693
Starting Page	20677
Page Count	17
File Format	HTM / HTML PDF
ISSN	00219258
Journal	Journal of Biological Chemistry (JBC)
Issue Number	30
Volume Number	289
DOI	10.1074/jbc.M114.568808
e-ISSN	1083351X
Language	English
Publisher	American Society for Biochemistry and Molecular Biology
Publisher Date	2014-07-25
Access Restriction	Open
Subject Keyword	Apoptosis C-Jun N-terminal kinase (JNK) Diabetes Endoplasmic Reticulum Stress (ER Stress) Unfolded Protein Response (UPR) Inositol-requiring Protein 1α (IRE1α) N-Myc Interactor (NMI) Pancreatic Beta Cells Molecular Bases of Disease
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry Molecular Biology

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