Novel Role for ESCRT-III Component CHMP4C in the Integrity of the Endocytic Network Utilized for Herpes Simplex Virus Envelopment.
Novel Role for ESCRT-III Component CHMP4C in the Integrity of the Endocytic Network Utilized for Herpes Simplex Virus Envelopment.
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DOI：
10.1128/mbio.02183-20
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发表时间：
2021-05-11
期刊：
影响因子：
6.4
通讯作者：
Elliott G
中科院分区：
文献类型：
--
作者：
Russell T;Samolej J;Hollinshead M;Smith GL;Kite J;Elliott G
包膜病毒利用细胞运输途径进行形态发生，为开发新的抗病毒疗法提供了潜在的空间。我们之前已经表明，单纯疱疹病毒1 （HSV1）利用循环内吞膜作为其包膜的来源，这一过程涉及四种Rab gtp酶。为了确定参与HSV1包膜的新因子，我们筛选了一个针对80多种人口贩运蛋白的小干扰RNA （siRNA）文库，包括外壳蛋白、接头蛋白、融合因子、裂变因子和Rab效应因子。耗尽11个因子使病毒产量降低20- 100倍，包括3个早期分泌途径蛋白、4个晚期分泌途径蛋白和4个内噬途径蛋白，其中3个是膜裂变因子。在11个靶点中选择了5个进行病毒感染的进一步分析，发现只有1个裂变因子CHMP4C缺失，而没有CHMP4A或CHMP4B同源物缺失，在形态发生的最后阶段减少了病毒的产生。chmp4c缺失的hsv1感染细胞的超微结构和共聚焦显微镜显示内吞膜积聚；广泛的循环管状，转铁蛋白受体阳性的核内体表明异常裂变；病毒包膜失败。未检测到对晚期内吞途径的影响，而外源性CHMP4C被证明定位于循环内体。综上所述，这些数据揭示了CHMP4C裂变因子在循环内体网络完整性中的新作用，这一作用已通过HSV1依赖这些膜获得其包膜而被揭示。
Enveloped viruses exploit cellular trafficking pathways for their morphogenesis, providing potential scope for the development of new antiviral therapies. We have previously shown that herpes simplex virus 1 (HSV1) utilizes recycling endocytic membranes as the source of its envelope, in a process involving four Rab GTPases. To identify novel factors involved in HSV1 envelopment, we have screened a small interfering RNA (siRNA) library targeting over 80 human trafficking proteins, including coat proteins, adaptor proteins, fusion factors, fission factors, and Rab effectors. The depletion of 11 factors reduced virus yields by 20- to 100-fold, including three early secretory pathway proteins, four late secretory pathway proteins, and four endocytic pathway proteins, three of which are membrane fission factors. Five of the 11 targets were chosen for further analysis in virus infection, where it was found that the absence of only 1, the fission factor CHMP4C, but not the CHMP4A or CHMP4B paralogues, reduced virus production at the final stage of morphogenesis. Ultrastructural and confocal microscopy of CHMP4C-depleted, HSV1-infected cells showed an accumulation of endocytic membranes; extensive tubulation of recycling, transferrin receptor-positive endosomes indicative of aberrant fission; and a failure in virus envelopment. No effect on the late endocytic pathway was detected, while exogenous CHMP4C was shown to localize to recycling endosomes. Taken together, these data reveal a novel role for the CHMP4C fission factor in the integrity of the recycling endosomal network, which has been unveiled through the dependence of HSV1 on these membranes for the acquisition of their envelopes.
流感病毒的宿主相互作用介绍了抗病毒药的新潜在靶标。
影响因子：
11.1
作者：
Shaw, Megan L.
通讯作者：
Shaw, Megan L.