The axonal sorting activity of pseudorabies virus Us9 protein depends on the state of neuronal maturation.
The axonal sorting activity of pseudorabies virus Us9 protein depends on the state of neuronal maturation.
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DOI：
10.1371/journal.ppat.1008861
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发表时间：
2020-12
期刊：
影响因子：
6.7
通讯作者：
Enquist LW
中科院分区：
文献类型：
--
作者：
Tanneti NS;Federspiel JD;Cristea IM;Enquist LW
α-疱疹病毒在受影响宿主的神经系统中建立终身感染;虽然这种感染仅限于健康宿主的外周神经元，但重新激活的病毒可以在受损个体的神经元回路内传播，例如传播到大脑，并导致不良的健康结果。伪狂犬病病毒（PRV）是一种α-疱疹病毒，需要病毒蛋白Us 9将病毒颗粒分选到轴突中并促进神经元扩散。us 9通过介导病毒颗粒与神经元转运机制的相互作用来分选病毒颗粒。在这里，我们报告说，Us 9介导的调节轴突分选也取决于神经元成熟的状态。具体而言，树突和轴突的发育伴随着影响神经元过程的蛋白质组学变化。未成熟的上级颈神经节神经元（SCG）具有缺乏成熟轴突标记的原始神经突。不成熟的SCG可以被PRV感染，但它们显示出明显降低的Us 9依赖的分选调节，并增加了Us 9独立的颗粒转运到神经突中。成熟的SCG具有相对较高丰度的囊泡运输机制的蛋白质特征。我们还确定了Us 9相关的神经元蛋白，可以有助于轴突分选和随后的顺行传播的病毒颗粒在轴突。我们发现，SMPD 4/nsMase 3，丰富的脂筏鞘磷脂酶，与Us 9和PRV的分类到轴突和神经元的传播，一个潜在的抗病毒功能的负调节。病毒的发病机制通常是年龄依赖性的，与成人相比，感染的胎儿和新生儿的结局更严重。随着神经元的老化和成熟，树突和轴突具有不同的功能，影响嗜神经病毒的复制和感染的神经元扩散。本研究探讨了周围神经系统神经元的神经元成熟，α-疱疹病毒的终身潜伏期和再激活的网站，影响伪狂犬病病毒的复制和神经元传播。表征感染的未成熟和成熟的原代培养的上级颈神经节神经元显示显着差异的蛋白质组成和细胞过程，影响Us 9的活性，所需的病毒蛋白分选病毒颗粒进入轴突。我们鉴定了在未成熟和成熟神经元中与Us 9相互作用的神经元和病毒蛋白。其中，我们证明了SMPD 4/nsMase 3，鞘磷脂酶膜组织和神经元功能的关键，调节PRV神经元的传播，防止衣壳协会与Us 9含有膜，提出了一个可能的抗病毒功能。
Alpha-herpesviruses establish a life-long infection in the nervous system of the affected host; while this infection is restricted to peripheral neurons in a healthy host, the reactivated virus can spread within the neuronal circuitry, such as to the brain, in compromised individuals and lead to adverse health outcomes. Pseudorabies virus (PRV), an alpha-herpesvirus, requires the viral protein Us9 to sort virus particles into axons and facilitate neuronal spread. Us9 sorts virus particles by mediating the interaction of virus particles with neuronal transport machinery. Here, we report that Us9-mediated regulation of axonal sorting also depends on the state of neuronal maturation. Specifically, the development of dendrites and axons is accompanied with proteomic changes that influence neuronal processes. Immature superior cervical ganglionic neurons (SCGs) have rudimentary neurites that lack markers of mature axons. Immature SCGs can be infected by PRV, but they show markedly reduced Us9-dependent regulation of sorting, and increased Us9-independent transport of particles into neurites. Mature SCGs have relatively higher abundances of proteins characteristic of vesicle-transport machinery. We also identify Us9-associated neuronal proteins that can contribute to axonal sorting and subsequent anterograde spread of virus particles in axons. We show that SMPD4/nsMase3, a sphingomyelinase abundant in lipid-rafts, associates with Us9 and is a negative regulator of PRV sorting into axons and neuronal spread, a potential antiviral function. Viral pathogenesis often is age-dependent, with more severe outcomes for infected fetuses and neonates compared to adults. As neurons age and mature, dendrites and axons polarize with distinct functions that affect neurotropic virus replication and neuronal spread of infection. This study investigates how neuronal maturation of peripheral nervous system neurons, the site of alpha-herpesvirus life-long latency and reactivation, affects replication and neuronal spread of pseudorabies virus. Characterization of infected immature and mature primary cultures of superior cervical ganglionic neurons revealed significant differences in protein composition and cellular processes that affected the activity of Us9, a viral protein required for sorting virus particles into axons. We identified neuronal and viral proteins that interact with Us9 in immature and mature neurons. Among these, we demonstrate that SMPD4/nsMase3, a sphingomyelinase critical for membrane organization and neuronal function, regulates PRV neuronal spread by preventing capsid association with Us9-containing membranes, presenting a possible antiviral function.
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影响因子：
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作者：
Curanovic, Dusica;Ch'ng, Toh Hean;Szpara, Moriah;Enquist, Lynn
通讯作者：
Enquist, Lynn
影响因子：
4.6
作者：
Nolte H;MacVicar TD;Tellkamp F;Krüger M
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Krüger M
影响因子：
30.3
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Kramer T;Greco TM;Taylor MP;Ambrosini AE;Cristea IM;Enquist LW
通讯作者：
Enquist LW
影响因子：
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通讯作者：
Vilo J
影响因子：
48
作者：
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通讯作者：
Nesvizhskii, Alexey I.