Title: A combined ″omics″ approach identifies NMI as a novel cytokine-induced regulator of IRE1α and JNK in pancreatic beta cells
Authors: Brozzi, Flora ×
Gerlo, Sarah
Grieco, Fabio Arturo
Nardelli, Tarlliza R
Lievens, Sam
Gysemans, Conny
Marselli, Lorella
Marchetti, Piero
Mathieu, Chantal
Tavernier, Jan
Eizirik, Decio L #
Issue Date: Jul-2014
Publisher: American Society for Biochemistry and Molecular Biology
Series Title: Journal of Biological Chemistry vol:289 issue:30 pages:20677-20693
Article number: jbc.M114.568808
Abstract: Type 1 diabetes (T1D) is an autoimmune disease with a strong inflammatory component. The cytokines interleukin-1β and interferon-γ contribute to beta cell apoptosis in T1D. These cytokines induce endoplasmic reticulum stress and the unfolded protein response (UPR), contributing to 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 IRE1α activation, and its signalling for beta cell ″adaptation″, ″stress response″ or ″apoptosis″ remain to be clarified. To address these questions we combined MAPPIT (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 non-obese diabetic (NOD) 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.
ISSN: 0021-9258
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Clinical and Experimental Endocrinology
Near Eastern Studies, Leuven
× corresponding author
# (joint) last author

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