Mucolipin-2 Cation Channel Increases Trafficking Efficiency of Endocytosed Viruses.
Mucolipin-2 Cation Channel Increases Trafficking Efficiency of Endocytosed Viruses.
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DOI：
10.1128/mbio.02314-17
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发表时间：
2018-01-30
期刊：
影响因子：
6.4
通讯作者：
Schoggins JW
中科院分区：
文献类型：
--
作者：
Rinkenberger N;Schoggins JW
受体介导的内吞作用是一种通常被病毒劫持进入细胞的细胞过程。某些病毒的进入阶段已得到很好的描述，但介导每一步的宿主因子尚不清楚。我们以前确定内体阳离子通道粘脂-2（MCOLN 2）作为促进病毒感染的宿主因子。在这里，我们分配MCOLN 2在调节病毒进入中的作用。我们表明，MCOLN 2特异性地促进病毒囊泡运输和随后的逃逸内体隔室。这种机制需要通道活性，独立于抗病毒信号传导发生，并且广泛适用于需要转运到晚期内体进行感染的包膜RNA病毒，包括甲型流感病毒、黄热病病毒和寨卡病毒。我们进一步确定了一种罕见的等位基因变异的人MCOLN 2，具有功能丧失的表型方面的病毒增强。这些发现建立了内体阳离子通道和病毒进入晚期之间的机制联系。病毒必须利用细胞过程来完成其生命周期。为了进入细胞，病毒经常利用细胞受体介导的内吞途径。越来越多的宿主蛋白质参与这些病毒摄取途径。在这里，我们描述了门控阳离子通道MCOLN 2在病毒进入的新作用。这种内体蛋白通过增强病毒通过内体系统运输的效率来调节病毒进入。因此，MCOLN 2介导的感染增强可能代表了病毒生命周期中的一个关键脆弱性，可以作为治疗干预的目标。
Receptor-mediated endocytosis is a cellular process commonly hijacked by viruses to enter cells. The stages of entry are well described for certain viruses, but the host factors that mediate each step are less well characterized. We previously identified endosomal cation channel mucolipin-2 (MCOLN2) as a host factor that promotes viral infection. Here, we assign a role for MCOLN2 in modulating viral entry. We show that MCOLN2 specifically promotes viral vesicular trafficking and subsequent escape from endosomal compartments. This mechanism requires channel activity, occurs independently of antiviral signaling, and broadly applies to enveloped RNA viruses that require transport to late endosomes for infection, including influenza A virus, yellow fever virus, and Zika virus. We further identify a rare allelic variant of human MCOLN2 that has a loss-of-function phenotype with respect to viral enhancement. These findings establish a mechanistic link between an endosomal cation channel and late stages of viral entry. Viruses must co-opt cellular processes to complete their life cycle. To enter cells, viruses frequently take advantage of cellular receptor-mediated endocytosis pathways. A growing number of host proteins are implicated in these viral uptake pathways. Here, we describe a new role for the gated cation channel MCOLN2 in viral entry. This endosomal protein modulates viral entry by enhancing the efficiency of viral trafficking through the endosomal system. Thus, MCOLN2-mediated enhancement of infection may represent a key vulnerability in the viral life cycle that could be targeted for therapeutic intervention.