Bunyavirus requirement for endosomal K+ reveals new roles of cellular ion channels during infection.
Bunyavirus requirement for endosomal K+ reveals new roles of cellular ion channels during infection.
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DOI：
10.1371/journal.ppat.1006845
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发表时间：
2018-01
期刊：
影响因子：
6.7
通讯作者：
Mankouri J
中科院分区：
文献类型：
--
作者：
Hover S;Foster B;Fontana J;Kohl A;Goldstein SAN;Barr JN;Mankouri J
为了繁殖和致病，病毒必须将其基因组从细胞外运输到胞浆中，这通常是通过内吞网络实现的。内体将病毒颗粒运送到特定的细胞目的地，病毒利用成熟的内吞囊泡不断变化的环境作为触发因素来调节基因组的释放。在此之前，我们证明了构成负义RNA病毒最大家族的几种布尼亚病毒，需要细胞钾(K+)通道的活性才能引起生产性感染。具体地说，我们展示了K+通道在病毒内体运输过程中的惊人作用。在这项研究中，我们使用了原型BunyaVirus，Bunyamwera病毒(BUNV)作为工具来理解为什么K+通道是这些病毒通过内吞网络进行进展所必需的。我们报告了三个主要发现：第一，生产了一种双重荧光标记的布尼亚病毒，以可视化活细胞中的病毒贩运。其次，我们证明了BUNV通过含有高[K+]的内体运输，这些K+离子影响病毒粒子的感染性。第三，我们发现抑制K+通道可以改变K+在内体系统中的分布，并阻止病毒在内体中的运输。这些数据表明，高内体[K+]是病毒感染所必需的关键信号，并由驻留在内体网络中的细胞K+通道控制。这突出了细胞K+通道是阻止病毒进入、感染和疾病的可用药靶点。为了穿透细胞和引起疾病，大多数病毒穿过细胞内吞网络并利用其环境来触发其遗传物质释放到细胞质中。内体的pH、病毒与受体的相互作用、蛋白水解性裂解和膜的脂质组成都被报道为内体的触发物。在这里，我们揭示了病毒进入的另一个关键内体触发因素的身份，即暴露于特定K+离子浓度的要求，我们证明这是由细胞K+通道调节的。我们证明，通过阻断K+通道，我们可以扰乱跨越内体系统的K+浓度，从而阻止病毒的传播。在这里，我们揭示了细胞K+通道作为一个新的药物靶点来抑制病毒进入，从而抑制疾病。
In order to multiply and cause disease a virus must transport its genome from outside the cell into the cytosol, most commonly achieved through the endocytic network. Endosomes transport virus particles to specific cellular destinations and viruses exploit the changing environment of maturing endocytic vesicles as triggers to mediate genome release. Previously we demonstrated that several bunyaviruses, which comprise the largest family of negative sense RNA viruses, require the activity of cellular potassium (K+) channels to cause productive infection. Specifically, we demonstrated a surprising role for K+ channels during virus endosomal trafficking. In this study, we have used the prototype bunyavirus, Bunyamwera virus (BUNV), as a tool to understand why K+ channels are required for progression of these viruses through the endocytic network. We report three major findings: First, the production of a dual fluorescently labelled bunyavirus to visualize virus trafficking in live cells. Second, we show that BUNV traffics through endosomes containing high [K+] and that these K+ ions influence the infectivity of virions. Third, we show that K+ channel inhibition can alter the distribution of K+ across the endosomal system and arrest virus trafficking in endosomes. These data suggest high endosomal [K+] is a critical cue that is required for virus infection, and is controlled by cellular K+ channels resident within the endosome network. This highlights cellular K+ channels as druggable targets to impede virus entry, infection and disease. To penetrate cells and cause disease most viruses traverse the cellular endocytic network and exploit its environment to trigger the release of their genetic material into the cytosol. Endosomal pH, virus-receptor interactions, proteolytic cleavage, and lipid composition of membranes have all been previously reported to act as endosomal triggers. Here, we reveal the identity of an additional critical endosomal trigger for virus entry, namely a requirement for exposure to specific K+ ion concentrations, which we demonstrate is regulated by cellular K+ channels. We show that by blocking K+ channels, we can disrupt the K+ concentration across the endosomal system, impeding virus trafficking. Here, we reveal cellular K+ channels as a new druggable target to inhibit virus entry, and thus disease.
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影响因子：
5.4
作者：
Shi, Xiaohong;van Mierlo, Joel T.;Elliott, Richard M.
通讯作者：
Elliott, Richard M.
影响因子：
5.4
作者：
Carvalho, Filomena A.;Carneiro, Fabiana A.;Santos, Nuno C.
通讯作者：
Santos, Nuno C.
影响因子：
30.3
作者：
Lozach PY;Mancini R;Bitto D;Meier R;Oestereich L;Overby AK;Pettersson RF;Helenius A
通讯作者：
Helenius A
DOI：
10.1073/pnas.1009997107
发表时间：
2010-08-31
影响因子：
11.1
作者：
Leiding, Thom;Wang, Jun;Arskold, Sindra Peterson
通讯作者：
Arskold, Sindra Peterson
影响因子：
7.3
作者：
Goldstein SA
通讯作者：
Goldstein SA