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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 [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>cyto<\/jats:sub>-mediated activation of CaMKK\u03b2 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.<\/jats:p>","DOI":"10.1038\/srep23130","type":"journal-article","created":{"date-parts":[[2016,3,15]],"date-time":"2016-03-15T10:34:48Z","timestamp":1458038088000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Dissection and integration of the autophagy signaling network initiated by bluetongue virus infection: crucial candidates ERK1\/2, Akt and AMPK"],"prefix":"10.1038","volume":"6","author":[{"given":"Shuang","family":"Lv","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing-Yuan","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"En-Cheng","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji-Kai","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong-Lai","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2016,3,15]]},"reference":[{"key":"BFsrep23130_CR1","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1016\/j.prevetmed.2011.04.005","volume":"102","author":"NJ Maclachlan","year":"2011","unstructured":"Maclachlan, N. 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