Alphavirus-induced hyperactivation of PI3K/AKT directs pro-viral metabolic changes.
Alphavirus-induced hyperactivation of PI3K/AKT directs pro-viral metabolic changes.
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DOI：
10.1371/journal.ppat.1006835
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发表时间：
2018-01
期刊：
影响因子：
6.7
通讯作者：
McInerney GM
中科院分区：
文献类型：
--
作者：
Mazzon M;Castro C;Thaa B;Liu L;Mutso M;Liu X;Mahalingam S;Griffin JL;Marsh M;McInerney GM
细胞代谢的病毒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中央能量代谢，但不同的病毒已被证明依赖于代谢激活的替代机制。相关病毒是否利用保守机制并诱导类似的代谢变化目前尚不清楚。在这项工作中，我们研究了两种甲病毒，塞姆利基森林病毒和罗斯河病毒，如何重新编程宿主代谢，并确定负责的分子机制。我们证明，在这两种情况下，在病毒蛋白nsP 3的YXXM基序的存在下是必要的结合PI 3 K调节亚基p85和激活AKT。这导致葡萄糖代谢向脂肪酸合成方向增加，尽管罗斯河病毒感染似乎涉及其他代谢活化机制。重要的是，不能激活AKT的罗斯河病毒突变体在体内具有减毒表型，表明PI 3 K/AKT的病毒激活有助于毒力和疾病。为了复制到高滴度，病毒需要从细胞中以氨基酸、核苷酸和脂质的形式提供足够的构建模块。为此，病毒已经进化出不同的机制来重新编程和利用宿主代谢来合成新的生物质。代谢活化相关途径的药理学抑制可代表治疗干预的机会。在这项研究中，我们探讨了甲病毒组的成员，包括塞姆利基森林病毒（SFV）和罗斯河病毒（RRV），如何改变宿主代谢。我们发现，这两种病毒通过激活PI 3 K/AKT途径激活细胞糖酵解。这种激活由病毒蛋白nsP 3中的YXXM基序介导，其结合PI 3 K并启动AKT信号传导。在SFV中，该基序中的突变阻止AKT活化，降低病毒诱导的代谢活性，并降低病毒复制。在人类病原体RRV中，相同的突变在体内引起不太严重的疾病。因此，我们得出结论，AKT激活感染这些病毒是一个重要的决定因素的致病性。
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. In order to replicate to high titres, viruses need a sufficient supply of building blocks from the cell in the form of amino acids, nucleotides and lipids. To this end, viruses have evolved different mechanisms to reprogram and exploit host metabolism towards the synthesis of new biomass. Pharmacological inhibition of pathways involved in metabolic activation can represent an opportunity for therapeutic intervention. In this study, we explore how members of the alphavirus group, including Semliki Forest virus (SFV) and Ross River virus (RRV), modify host metabolism. We discover that both viruses activate cellular glycolysis by activating the PI3K/AKT pathway. This activation is mediated by a YXXM motif in the viral protein nsP3, which binds to PI3K and initiates AKT signalling. In SFV, mutations in this motif prevent AKT activation, reduce virus-induced metabolic activity, and lower viral replication. In the human pathogen RRV the same mutation causes less severe disease in vivo. We therefore conclude that AKT activation during infection with these viruses is an important determinant of pathogenicity.
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影响因子：
29
作者：
Pavlova NN;Thompson CB
通讯作者：
Thompson CB
影响因子：
5.4
作者：
Ripoli, Maria;D'Aprile, Annamaria;Piccoli, Claudia
通讯作者：
Piccoli, Claudia
影响因子：
--
作者：
Castro C;Krumsiek J;Lehrbach NJ;Murfitt SA;Miska EA;Griffin JL
通讯作者：
Griffin JL
影响因子：
--
作者：
Olivia, Lwande Wesula;Obanda, Vincent;Evander, Magnus
通讯作者：
Evander, Magnus
影响因子：
3.8
作者：
Findlay, James S.;Ulaeto, David
通讯作者：
Ulaeto, David