Laboratory of Experimental Medicine, Medical Faculty, Université Libre de Bruxelles, Brussels, Belgium.
PLoS Pathog. 2011 Sep;7(9):e1002267. doi: 10.1371/journal.ppat.1002267. Epub 2011 Sep 22.
The rise in type 1 diabetes (T1D) incidence in recent decades is probably related to modifications in environmental factors. Viruses are among the putative environmental triggers of T1D. The mechanisms regulating beta cell responses to viruses, however, remain to be defined. We have presently clarified the signaling pathways leading to beta cell apoptosis following exposure to the viral mimetic double-stranded RNA (dsRNA) and a diabetogenic enterovirus (Coxsackievirus B5). Internal dsRNA induces cell death via the intrinsic mitochondrial pathway. In this process, activation of the dsRNA-dependent protein kinase (PKR) promotes eIF2α phosphorylation and protein synthesis inhibition, leading to downregulation of the antiapoptotic Bcl-2 protein myeloid cell leukemia sequence 1 (Mcl-1). Mcl-1 decrease results in the release of the BH3-only protein Bim, which activates the mitochondrial pathway of apoptosis. Indeed, Bim knockdown prevented both dsRNA- and Coxsackievirus B5-induced beta cell death, and counteracted the proapoptotic effects of Mcl-1 silencing. These observations indicate that the balance between Mcl-1 and Bim is a key factor regulating beta cell survival during diabetogenic viral infections.
近年来，1 型糖尿病（T1D）发病率的上升可能与环境因素的改变有关。病毒是 T1D 的潜在环境触发因素之一。然而，调节β细胞对病毒反应的机制仍有待确定。我们目前已经阐明了β细胞在暴露于病毒模拟物双链 RNA（dsRNA）和一种致糖尿病肠病毒（柯萨奇病毒 B5）后发生细胞凋亡的信号通路。内源性 dsRNA 通过内在的线粒体途径诱导细胞死亡。在这个过程中，双链 RNA 依赖性蛋白激酶（PKR）的激活促进 eIF2α 的磷酸化和蛋白质合成的抑制，导致抗凋亡蛋白 Bcl-2 家族成员 1（Mcl-1）的下调。Mcl-1 的减少导致仅含有 BH3 结构域的蛋白 Bim 的释放，从而激活线粒体凋亡途径。事实上，Bim 的敲低阻止了 dsRNA 和柯萨奇病毒 B5 诱导的β细胞死亡，并抵消了 Mcl-1 沉默的促凋亡作用。这些观察结果表明，Mcl-1 和 Bim 之间的平衡是调节β细胞在致糖尿病病毒感染期间存活的关键因素。
