A Pseudorabies Virus Serine/Threonine Kinase, US3, Promotes Retrograde Transport in Axons via Akt/mToRC1.
A Pseudorabies Virus Serine/Threonine Kinase, US3, Promotes Retrograde Transport in Axons via Akt/mToRC1.
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DOI：
10.1128/jvi.01752-21
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发表时间：
2022-03-09
影响因子：
5.4
通讯作者：
Enquist LW
中科院分区：
文献类型：
--
作者：
Esteves AD;Koyuncu OO;Enquist LW
α疱疹病毒（AHV）感染外周轴突是在宿主体内建立终身感染的关键阶段。进入轴突的细胞质后，AHV 核衣壳和相关的内被膜蛋白必须参与细胞逆行运输机制，以促进病毒粒子成分长距离运动至细胞核。目前概述这一过程的模型并不完整，需要进一步研究以发现所涉及的所有病毒和细胞决定因素以及事件的暂时性。使用改良的三室系统，我们发现了伪狂犬病病毒 (PRV) 丝氨酸/苏氨酸激酶 US3 在促进核衣壳有效逆行运输中的新作用。我们发现，在存在和不存在功能性 US3 激酶的情况下，核衣壳的运输速度相似。然而，当 US3 不存在时，移动的核衣壳较少，并且它们在停止前移动的时间较短，这表明 US3 是核衣壳与逆行运输机制有效结合所必需的。这导致 12 小时后到达细胞体产生有效感染的核衣壳减少。此外，US3 早在感染后 1 小时 (hpi) 就通过刺激磷脂酰肌醇 3-激酶 (PI3K)/Akt-mToRC1 途径负责诱导轴突局部翻译。这些数据描述了 US3 在 AHV 感染期间诱导轴突局部翻译中的新作用，这是核衣壳转运至细胞体的关键步骤。重要性 神经元是高度极化的细胞，其轴突长度可达厘米。外围轴突与远处细胞体之间的通讯是一个相对缓慢的过程，涉及化学信使的主动运输。轴突需要对细胞外刺激做出快速反应。轴突内存在的受抑制 mRNA 的翻译发生，以实现独立于细胞体的快速、局部反应。 AHV 已经进化出一种劫持轴突局部翻译的方法，以促进轴突向细胞核的运输。我们已经确定了参与轴突翻译诱导的细胞机制和病毒成分。 PRV 的 US3 丝氨酸/苏氨酸激酶在感染早期激活 Akt-mToRC1 信号通路，以促进轴突翻译。当 US3 不存在时，移动核衣壳的数量及其持续合成能力会减少，这表明 US3 活性是核衣壳与逆行运输机制有效结合所必需的。
Infection of peripheral axons by alpha herpesviruses (AHVs) is a critical stage in establishing a lifelong infection in the host. Upon entering the cytoplasm of axons, AHV nucleocapsids and associated inner-tegument proteins must engage the cellular retrograde transport machinery to promote the long-distance movement of virion components to the nucleus. The current model outlining this process is incomplete, and further investigation is required to discover all viral and cellular determinants involved as well as the temporality of the events. Using a modified trichamber system, we have discovered a novel role of the pseudorabies virus (PRV) serine/threonine kinase US3 in promoting efficient retrograde transport of nucleocapsids. We discovered that transporting nucleocapsids move at similar velocities in both the presence and absence of a functional US3 kinase; however, fewer nucleocapsids are moving when US3 is absent, and they move for shorter periods of time before stopping, suggesting that US3 is required for efficient nucleocapsid engagement with the retrograde transport machinery. This led to fewer nucleocapsids reaching the cell bodies to produce a productive infection 12 h later. Furthermore, US3 was responsible for the induction of local translation in axons as early as 1 h postinfection (hpi) through the stimulation of a phosphatidylinositol 3-kinase (PI3K)/Akt-mToRC1 pathway. These data describe a novel role for US3 in the induction of local translation in axons during AHV infection, a critical step in transport of nucleocapsids to the cell body. IMPORTANCE Neurons are highly polarized cells with axons that can reach centimeters in length. Communication between axons at the periphery and the distant cell body is a relatively slow process involving the active transport of chemical messengers. There is a need for axons to respond rapidly to extracellular stimuli. Translation of repressed mRNAs present within the axon occurs to enable rapid, localized responses independently of the cell body. AHVs have evolved a way to hijack local translation in the axons to promote their transport to the nucleus. We have determined the cellular mechanism and viral components involved in the induction of axonal translation. The US3 serine/threonine kinase of PRV activates Akt-mToRC1 signaling pathways early during infection to promote axonal translation. When US3 is not present, the number of moving nucleocapsids and their processivity are reduced, suggesting that US3 activity is required for efficient engagement of nucleocapsids with the retrograde transport machinery.