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
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
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DOI：
10.1074/jbc.m114.568808
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发表时间：
2014-07-25
影响因子：
4.8
通讯作者：
Eizirik, Decio L.
中科院分区：
文献类型：
--
作者：
Brozzi, Flora;Gerlo, Sarah;Eizirik, Decio L.
1型糖尿病是一种自身免疫性疾病，具有强烈的炎症成分。细胞因子IL-1β和干扰素-γ在1型糖尿病的β细胞凋亡中起重要作用。这些细胞因子诱导内质网应激和未折叠蛋白反应(UPR)，导致β细胞的损失。IRE1α是UPR的介体之一，在β细胞中触发胰岛素降解和炎症，对于UPR从生理性到病理性的转变至关重要。调控肌醇需要蛋白1α(IRE1α)激活及其信号转导β细胞“适应”、“应激反应”或“凋亡”的机制仍有待阐明。为了解决这些问题，我们结合了哺乳动物蛋白质-蛋白质相互作用，基于TRAP的IRE1α相互作用组，以及暴露于促炎细胞因子下的人和啮齿动物β细胞的功能基因组分析，以确定新的细胞因子诱导的IRE1α调节因子。在此基础上，我们发现N-Myc相互作用蛋白(NMI)在啮齿动物和人胰岛β细胞中是IRE1α相互作用/调节蛋白。在患有胰岛素炎的非肥胖糖尿病小鼠的胰岛以及在体外暴露于促炎症细胞因子IL-1β和干扰素-γ的啮齿动物或人类β细胞中，检测到NMI的表达增加。详细的机制研究表明，NMI负性调节啮齿动物和人胰腺β细胞中IRE1α依赖的JNK激活和凋亡。总之，通过结合组学方法，我们发现NMI诱导是一种新的负反馈机制，它可以减少细胞因子暴露的β细胞中IRE1α依赖的JNK激活和凋亡。
Type 1 diabetes is an autoimmune disease with a strong inflammatory component. The cytokines interleukin-1 beta and interferon-gamma 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. IRE1 alpha, 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 1 alpha (IRE1 alpha) 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 IRE1 alpha interactome and functional genomic analysis of human and rodent beta cells exposed to pro-inflammatory cytokines to identify novel cytokine-induced regulators of IRE1 alpha. Based on this approach, we identified N-Myc interactor (NMI) as an IRE1 alpha-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-1 beta and interferon-gamma. Detailed mechanistic studies demonstrated that NMI negatively modulates IRE1 alpha-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 IRE1 alpha-dependent activation of JNK and apoptosis in cytokine-exposed beta cells.