Type 1 diabetes (T1D) is an autoimmune disease characterized by islet inflammation and progressive pancreatic β cell destruction. The disease is triggered by a combination of genetic and environmental factors, but the mechanisms leading to the triggering of early innate and late adaptive immunity and consequent progressive pancreatic β cell death remain unclear. The insulin-producing β cells are active secretory cells and are thus particularly sensitive to endoplasmic reticulum (ER) stress. ER stress plays an important role in the pathologic pathway leading to autoimmunity, islet inflammation, and β cell death. We show here that group B coxsackievirus (CVB) infection, a putative causative factor for T1D, induces a partial ER stress in rat and human β cells. The activation of the PERK/ATF4/CHOP branch is blunted while the IRE1α branch leads to increased spliced XBP1 expression and c-Jun N-terminal kinase (JNK) activation. Interestingly, JNK1 activation is essential for CVB amplification in both human and rat β cells. Furthermore, a chemically induced ER stress preceding viral infection increases viral replication, in a process dependent on IRE1α activation. Our findings show that CVB tailors the unfolded protein response in β cells to support their replication, preferentially triggering the pro-viral IRE1α/XBP1s/JNK1 pathway while blocking the pro-apoptotic PERK/ATF4/CHOP pathway.

中文翻译：

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柯萨奇病毒B调节了胰腺β细胞中未折叠的蛋白质应答，以促进病毒的扩增。

1型糖尿病（T1D）是一种自身免疫性疾病，其特征在于胰岛炎症和进行性胰腺β细胞破坏。该疾病是由遗传和环境因素共同引发的，但导致早期先天和晚期适应性免疫以及随后进行性胰腺β细胞死亡的触发机制尚不清楚。产生胰岛素的β细胞是活性分泌细胞，因此对内质网（ER）应激特别敏感。ER应激在导致自身免疫，胰岛炎症和β细胞死亡的病理途径中起着重要作用。我们在这里显示，B型柯萨奇病毒（CVB）感染是T1D的假定诱因，在大鼠和人β细胞中诱导部分ER应激。PERK / ATF4 / CHOP分支的激活减弱，而IRE1α分支导致增加的剪接XBP1表达和c-Jun N端激酶（JNK）激活。有趣的是，JNK1激活对于人和大鼠β细胞中CVB的扩增至关重要。此外，在病毒感染之前，化学诱导的内质网应激会在依赖IRE1α激活的过程中增加病毒复制。我们的研究结果表明，CVB可以调节β细胞中未折叠的蛋白反应以支持其复制，优先触发促病毒的IRE1α/ XBP1s / JNK1途径，同时阻止促凋亡的PERK / ATF4 / CHOP途径。在取决于IRE1α激活的过程中，病毒感染前化学诱导的ER应激会增加病毒复制。我们的研究结果表明，CVB可以调节β细胞中未折叠的蛋白反应以支持其复制，优先触发促病毒的IRE1α/ XBP1s / JNK1途径，同时阻止促凋亡的PERK / ATF4 / CHOP途径。在取决于IRE1α激活的过程中，病毒感染前化学诱导的ER应激会增加病毒复制。我们的研究结果表明，CVB可以调节β细胞中未折叠的蛋白反应以支持其复制，优先触发促病毒的IRE1α/ XBP1s / JNK1途径，同时阻止促凋亡的PERK / ATF4 / CHOP途径。