Genome-wide RNAi screen identifies SEC61A and VCP as conserved regulators of Sindbis virus entry.
Genome-wide RNAi screen identifies SEC61A and VCP as conserved regulators of Sindbis virus entry.
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DOI：
10.1016/j.celrep.2013.11.028
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发表时间：
2013-12-26
期刊：
影响因子：
8.8
通讯作者：
Cherry S
中科院分区：
文献类型：
--
作者：
Panda D;Rose PP;Hanna SL;Gold B;Hopkins KC;Lyde RB;Marks MS;Cherry S
甲型病毒是一大类昆虫传播的人类病原体，对感染所需的宿主因素知之甚少。为了确定这些因素，我们使用果蝇模型细胞进行了全基因组RNAi筛选，并验证了94个影响典型甲型病毒辛德比斯病毒(SINV)感染的基因。我们发现SEC61a和VCP在促进昆虫和哺乳动物的SINV进入方面发挥了保守的作用。SEC61a和VCP选择性地调节进入受体NRAMP2的运输，这些蛋白的丢失或药物抑制导致改变的NRAMP2运输到溶酶体室和溶酶体内的蛋白水解性消化。NRAMP2是细胞内主要的铁转运体，NRAMP2的缺失减弱了细胞内铁的转运。因此，这项研究揭示了与感染和铁稳态有关的新基因和途径，这些基因和途径可能成为抗病毒治疗或铁失衡障碍的靶点。
Alphaviruses are a large class of insect-borne human pathogens and little is known about the host factor requirements for infection. To identify such factors we performed a genome-wide RNAi screen using model Drosophila cells and validated 94 genes that impacted infection of Sindbis virus (SINV), the prototypical alphavirus. We identified a conserved role for SEC61A and VCP in facilitating SINV entry in insects and mammals. SEC61A and VCP selectively regulate trafficking of the entry receptor NRAMP2, and loss of these proteins, or pharmacological inhibition, leads to altered NRAMP2 trafficking to lysosomal compartments, and proteolytic digestion within lysosomes. NRAMP2 is the major iron transporter in cells, and loss of NRAMP2 attenuates intracellular iron transport. Thus, this study reveals new genes and pathways involved in both infection and iron homeostasis that may serve as targets for antiviral therapeutics or for iron imbalance disorders.
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