MRC Laboratory for Molecular Cell Biology, University College London, London, United Kingdom.
Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom.
PLoS Pathog. 2018 Jan 29;14(1):e1006835. doi: 10.1371/journal.ppat.1006835. eCollection 2018 Jan.
Virus reprogramming of cellular metabolism is recognised as a critical determinant for viral growth. While most viruses appear to activate central energy metabolism, different viruses have been shown to rely on alternative mechanisms of metabolic activation. Whether related viruses exploit conserved mechanisms and induce similar metabolic changes is currently unclear. In this work we investigate how two alphaviruses, Semliki Forest virus and Ross River virus, reprogram host metabolism and define the molecular mechanisms responsible. We demonstrate that in both cases the presence of a YXXM motif in the viral protein nsP3 is necessary for binding to the PI3K regulatory subunit p85 and for activating AKT. This leads to an increase in glucose metabolism towards the synthesis of fatty acids, although additional mechanisms of metabolic activation appear to be involved in Ross River virus infection. Importantly, a Ross River virus mutant that fails to activate AKT has an attenuated phenotype in vivo, suggesting that viral activation of PI3K/AKT contributes to virulence and disease.
病毒对细胞代谢的重编程被认为是病毒生长的关键决定因素。虽然大多数病毒似乎激活了中心能量代谢，但已经证明不同的病毒依赖于代谢激活的替代机制。目前尚不清楚相关病毒是否利用保守机制并诱导类似的代谢变化。在这项工作中，我们研究了两种甲病毒，森林病毒和罗斯河病毒，如何重编程宿主代谢并定义负责的分子机制。我们证明，在这两种情况下，病毒蛋白 nsP3 中的 YXXM 基序的存在对于与 PI3K 调节亚基 p85 的结合以及激活 AKT 是必需的。这导致葡萄糖代谢向脂肪酸合成的增加，尽管罗斯河病毒感染似乎涉及其他代谢激活机制。重要的是，一种不能激活 AKT 的罗斯河病毒突变体在体内表现出减毒表型，这表明病毒激活 PI3K/AKT 有助于毒力和疾病。
