Chikungunya virus-induced autophagy delays caspase-dependent cell death.
Chikungunya virus-induced autophagy delays caspase-dependent cell death.
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DOI：
10.1084/jem.20110996
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发表时间：
2012-05-07
期刊：
影响因子：
--
通讯作者：
Albert ML
中科院分区：
文献类型：
--
作者：
Joubert PE;Werneke SW;de la Calle C;Guivel-Benhassine F;Giodini A;Peduto L;Levine B;Schwartz O;Lenschow DJ;Albert ML
基孔肯雅病毒通过触发ER和氧化应激诱导自噬，并且这种自噬限制细胞凋亡和病毒繁殖。自噬是一种重要的生存途径，参与宿主对感染的应答。研究基孔肯雅病毒（CHIKV），在印度，东南亚和南欧的主要流行病的病原体，我们揭示了一种新的机制，自噬限制细胞死亡和感染后的死亡率。我们使用生物化学研究和单细胞多光谱测定来证明直接感染触发细胞凋亡和自噬。CHIKV诱导的自噬是由内质网和氧化应激途径的独立诱导介导的。这些细胞反应通过诱导IRE 1 α-XBP-1通路以及ROS介导的mTOR抑制来延迟凋亡性细胞死亡。自噬基因的沉默导致增强的内在和外在的细胞凋亡，有利于培养细胞中的病毒繁殖。为我们的研究结果的相关性提供了体内证据，Atg 16 LHM小鼠显示出降低的自噬水平，表现出增加的致死率，并对CHIKV诱导的细胞凋亡表现出更高的敏感性。基于动力学研究和观察，细胞凋亡和自噬的功能是相互排斥的，我们得出结论，自噬抑制半胱天冬酶依赖的细胞死亡，但最终被病毒复制压倒。我们的研究表明，自噬诱导剂可能限制急性基孔肯雅病的发病机制。
Chikungunya virus induces autophagy by triggering ER and oxidative stress, and this autophagy restricts apoptosis and viral propagation. Autophagy is an important survival pathway and can participate in the host response to infection. Studying Chikungunya virus (CHIKV), the causative agent of a major epidemic in India, Southeast Asia, and southern Europe, we reveal a novel mechanism by which autophagy limits cell death and mortality after infection. We use biochemical studies and single cell multispectral assays to demonstrate that direct infection triggers both apoptosis and autophagy. CHIKV-induced autophagy is mediated by the independent induction of endoplasmic reticulum and oxidative stress pathways. These cellular responses delay apoptotic cell death by inducing the IRE1α–XBP-1 pathway in conjunction with ROS-mediated mTOR inhibition. Silencing of autophagy genes resulted in enhanced intrinsic and extrinsic apoptosis, favoring viral propagation in cultured cells. Providing in vivo evidence for the relevance of our findings, Atg16LHM mice, which display reduced levels of autophagy, exhibited increased lethality and showed a higher sensitivity to CHIKV-induced apoptosis. Based on kinetic studies and the observation that features of apoptosis and autophagy were mutually exclusive, we conclude that autophagy inhibits caspase-dependent cell death but is ultimately overwhelmed by viral replication. Our study suggests that inducers of autophagy may limit the pathogenesis of acute Chikungunya disease.
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