Dissection and integration of the autophagy signaling network initiated by bluetongue virus infection: crucial candidates ERK1/2, Akt and AMPK.
Dissection and integration of the autophagy signaling network initiated by bluetongue virus infection: crucial candidates ERK1/2, Akt and AMPK.
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蓝舌病毒感染引发的自噬信号网络的剖析和整合：关键候选者 ERK1/2、Akt 和 AMPK
DOI：
10.1038/srep23130
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发表时间：
2016-03-15
影响因子：
4.6
通讯作者：
Wu DL
中科院分区：
文献类型：
--
作者：
Lv S;Xu QY;Sun EC;Zhang JK;Wu DL
蓝舌病毒（BTV）是一种复杂的双链节段RNA病毒，已发现其启动细胞自噬以获得自身益处。在这里，为了理解潜在的机制，我们首先系统地解剖了BTV诱导的自噬的确切信号网络。我们发现，BTV 1感染抑制了关键枢纽mTOR的活性，随后导致下游p70 S6 K抑制和自噬启动。然后，我们探索了mTOR的上游调节因子，并通过一系列测定分析了它们的活性。我们发现BTV1诱导的自噬不依赖于ERK 1/2信号通路。然而，发现BTV 1诱导的PI3K/Akt抑制部分负责mTOR失活和随后的自噬启动。此外，我们意外地发现AMPK似乎在BTV1诱导的自噬中发挥更重要的作用。细胞内[Ca 2 +]浓度升高介导的CaMKK β激活可有效地控制AMPK的激活，AMPK通过抑制mTOR而正向调节自噬。我们必须强调的是，TSC 2是上游Akt或AMPK和下游mTOR之间通过其磷酸化的致命介质。综上所述，我们的数据表明BTV1诱导的Akt-TSC2-mTOR通路的抑制和AMPK-TSC2-mTOR通路的上调都有助于自噬的启动并进一步有利于病毒复制。
Bluetongue virus (BTV), a complex double-stranded segmented RNA virus, has been found to initiate cellular autophagy for its own benefit. Here, with a view to understanding the underlying mechanisms, we first systematically dissected the exact signaling network in BTV-induced autophagy. We found that the activity of mTOR, a crucial pivot, was inhibited by BTV1 infection, subsequently leading to downstream p70S6K suppression and autophagy initiation. We then explored the upstream regulators of mTOR and analyzed their activities via a series of assays. We found BTV1-induced autophagy to be independent of the ERK1/2 signaling pathway. However, the BTV1-induced inhibition of PI3K/Akt was found to be partially responsible for mTOR inactivation and subsequent autophagy initiation. Furthermore, we found unexpectedly that AMPK seemed to play a more important role in BTV1-induced autophagy. Elevated [Ca2+]cyto-mediated activation of CaMKKβ exactly managed the activation of AMPK, which then positively regulated autophagy through suppressing mTOR. We must emphasize that TSC2 is a fatal mediator between upstream Akt or AMPK and downstream mTOR through its phosphorylation. Taken together, our data suggested that the BTV1-induced inhibition of the Akt-TSC2-mTOR pathway and the upregulation of the AMPK-TSC2-mTOR pathway both contributed to autophagy initiation and further favored virus replication.