The unfolded protein response induced by Tembusu virus infection
The unfolded protein response induced by Tembusu virus infection
复制标题
天布苏病毒感染诱导的未折叠蛋白反应
DOI：
10.1186/s12917-019-1781-4
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发表时间：
2019-01
影响因子：
2.6
通讯作者：
Lijiao Zhang
中科院分区：
文献类型：
--
作者：
Yin Li;Yuzhuo Liu;Huili Wang;Kaikai Han;Xinmei Huang;Dongmin Zhao;Jing Yang;Qingtao Liu;Lijiao Zhang
研究背景坦布苏病毒（Tembusuvirus，TMUV）是黄病毒属（Flavivirus）病毒，可引起家禽产蛋量下降和神经系统疾病，黄病毒的复制依赖于宿主内质网（Endoplasmic reticulum，ER），并诱导内质网应激，激活细胞未折叠蛋白反应（Unfolded protein response，UPR），UPR是一条重要的信号通路，调节病毒致病和先天免疫等多种生物学功能。然而，TUV诱导的UPR激活的机制仍不清楚。ResultsIn这项研究中，我们系统地研究了TUV感染的BHK-21细胞中的三个UPR通路。结果表明，葡萄糖相关蛋白78（GRP 78）和GRP 94在TMUV感染过程中表达上调。然后，我们证明了TMUV在感染的早期激活PERK通路，导致ATF 4、GADD 34和CHOP的上调，CHOP诱导导致caspase-3激活。我们还发现IRE 1途径被激活，导致X盒结合蛋白1（XBP 1）mRNA的剪接和p58 IPK的表达增强。最后，我们观察到ATF 6的表达和ER应激反应元件的活性增加，表明ATF 6通路的刺激。此外，ATF 6通路激活与下游伴侣钙连接蛋白、钙网蛋白、ERp 57和PDI的诱导相关。在TMV感染的DF-1细胞中，GRP 78和sXBP 1水平显著升高，UPR活性也显著增强。结论TMUV感染诱导的内质网应激激活了UPR的3个分支，这是首次报道，为阐明TMUV的发病机制、了解TMUV感染的内在机制以及宿主的反应奠定了基础。
BackgroundTembusu virus (TMUV), classified in the genusFlavivirus, causes reduced egg production and neurological problems in poultry.Flavivirusreplication depends on the host endoplasmic reticulum (ER) and induces ER stress that leads to activation of the cellular unfolded protein response (UPR), an important signalling pathway that regulates many biological functions involved in viral pathogenesis and innate immunity. However, the mechanism of TMUV-induced UPR activation remains unclear.ResultsIn this study, we systematically investigated the three UPR pathways in TMUV-infected BHK-21 cells. Our results showed that expression of glucose-related protein 78 (GRP78) and GRP94 was upregulated during the course of TMUV infection. We then demonstrated that TMUV activated the PERK pathway in the early stage of infection, resulting in upregulation of ATF4, GADD34 and CHOP, with CHOP induction leading to caspase-3 activation. We also found the IRE1 pathway to be activated, leading to splicing of X box binding protein 1 (XBP1) mRNA and enhanced expression of p58IPK. Finally, we observed increased expression of ATF6 and activity of ER stress-response elements, suggesting stimulation of the ATF6 pathway. In addition, ATF6 pathway activation correlated with the induction of downstream chaperones calnexin, calreticulin, ERp57 and PDI. UPR activity was also observed by the marked elevation in GRP78 and sXBP1 levels in TMUV-infected DF-1 cells.ConclusionsThis is the first report that TMUV infection-induced ER stress activates three branches of the UPR, and these results lay the foundation for elucidating the pathogenesis of TMUV and understanding the inherent mechanism of TMUV infection as well as the host response.
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影响因子：
4.8
作者：
Li S;Li X;Zhang L;Wang Y;Yu X;Tian K;Su W;Han B;Su J
通讯作者：
Su J
影响因子：
4.6
作者：
Lee YR;Kuo SH;Lin CY;Fu PJ;Lin YS;Yeh TM;Liu HS
通讯作者：
Liu HS
影响因子：
4.8
作者：
Wu YP;Chang CM;Hung CY;Tsai MC;Schuyler SC;Wang RY
通讯作者：
Wang RY
影响因子：
64.5
作者：
Yoshida, H;Matsui, T;Mori, K
通讯作者：
Mori, K
影响因子：
5.4
作者：
Tardif, KD;Mori, K;Siddiqui, A
通讯作者：
Siddiqui, A