Dengue virus-induced ER stress is required for autophagy activation, viral replication, and pathogenesis both in vitro and in vivo.
Dengue virus-induced ER stress is required for autophagy activation, viral replication, and pathogenesis both in vitro and in vivo.
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DOI：
10.1038/s41598-017-18909-3
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发表时间：
2018-01-11
影响因子：
4.6
通讯作者：
Liu HS
中科院分区：
文献类型：
--
作者：
Lee YR;Kuo SH;Lin CY;Fu PJ;Lin YS;Yeh TM;Liu HS
登革病毒(DENV)利用内质网进行复制和组装。内质网腔内未折叠蛋白的积聚导致内质网应激和未折叠蛋白反应(UPR)。UPR的三个分支在时间上调节DENV感染。此外，内质网应激还可以诱导自噬。DENV感染可诱导自噬，在病毒复制中起促进作用，已有报道。然而，内质网应激在DENV诱导的自噬、病毒滴度和发病机制中的作用仍不清楚。在这里，我们揭示了内质网应激及其下游的UPR对于DENV诱导的各种人类细胞的自噬是不可或缺的。我们证明了在DENV感染后，PERK-eIF2α和IRE1α-JNK信号通路增加了自噬和病毒载量。然而，ATF6相关途径对自噬和病毒复制没有影响。IRE1JNK下游分子Bcl2被激活的α磷酸化，并与在自噬激活中起关键作用的Beclin 1解离。这些发现证实，在体内存在JNK抑制剂的情况下，病毒滴度降低，疾病症状减轻，存活率延长。综上所述，我们首次揭示了DENV2诱导的内质网应激通过体外和体内两条UPR信号通路增加自噬活性、DENV复制和致病。
Dengue virus (DENV) utilizes the endoplasmic reticulum (ER) for replication and assembling. Accumulation of unfolded proteins in the ER lumen leads to ER stress and unfolded protein response (UPR). Three branches of UPRs temporally modulated DENV infection. Moreover, ER stress can also induce autophagy. DENV infection induces autophagy which plays a promotive role in viral replication has been reported. However, the role of ER stress in DENV-induced autophagy, viral titer, and pathogenesis remain unclear. Here, we reveal that ER stress and its downstream UPRs are indispensable for DENV-induced autophagy in various human cells. We demonstrate that PERK-eIF2α and IRE1α-JNK signaling pathways increased autophagy and viral load after DENV infection. However, ATF6-related pathway showed no effect on autophagy and viral replication. IRE1α-JNK downstream molecule Bcl-2 was phosphorylated by activated JNK and dissociated from Beclin 1, which playing a critical role in autophagy activation. These findings were confirmed as decreased viral titer, attenuated disease symptoms, and prolonged survival rate in the presence of JNK inhibitor in vivo. In summary, we are the first to reveal that DENV2-induced ER stress increases autophagy activity, DENV replication, and pathogenesis through two UPR signaling pathways both in vitro and in vivo.
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影响因子：
5.4
作者：
Ambrose, Rebecca L.;Mackenzie, Jason M.
通讯作者：
Mackenzie, Jason M.
影响因子：
30.3
作者：
Heaton NS;Randall G
通讯作者：
Randall G
影响因子：
11.2
作者：
Clarke R;Cook KL;Hu R;Facey CO;Tavassoly I;Schwartz JL;Baumann WT;Tyson JJ;Xuan J;Wang Y;Wärri A;Shajahan AN
通讯作者：
Shajahan AN
影响因子：
2
作者：
Hausmann M
通讯作者：
Hausmann M
DOI：
10.1073/pnas.0802865105
发表时间：
2008-05-27
影响因子：
11.1
作者：
Jang, Saebyeol;Kelley, Keith W.;Johnson, Rodney W.
通讯作者：
Johnson, Rodney W.