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

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...

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Published in:The Journal of biological chemistry 2014-07, Vol.289 (30), p.20677-20693
Main Authors: 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.
Format: Article
Language:English
Subjects:
Apoptosis
c-Jun N-terminal kinase (JNK)
Cell Biology
Diabetes
Endoplasmic Reticulum Stress (ER Stress)
Inositol-requiring Protein 1α (IRE1α)
N-Myc Interactor (NMI)
Pancreatic Beta Cells
Unfolded Protein Response (UPR)
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Summary: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. Background: Cytokine-induced IRE1α activation regulates adaptive/pro-apoptotic endoplasmic reticulum (ER) stress transition in type 1 diabetes (T1D). Results: The IRE1α-binding protein NMI modulates JNK activation and apoptosis in beta cells. Conclusion: NMI induction is a novel negative feedback mechanism regulating ER stress and apoptosis in cytokine-exposed beta cells. Significance: Clarifying cytokine modulation of ER stress may provide information to protect beta cells in early T1D.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M114.568808