TMEM41B Is a Pan-flavivirus Host Factor.
TMEM41B Is a Pan-flavivirus Host Factor.
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DOI：
10.1016/j.cell.2020.12.005
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发表时间：
2021-01-07
期刊：
影响因子：
64.5
通讯作者：
Rice CM
中科院分区：
文献类型：
--
作者：
Hoffmann HH;Schneider WM;Rozen-Gagnon K;Miles LA;Schuster F;Razooky B;Jacobson E;Wu X;Yi S;Rudin CM;MacDonald MR;McMullan LK;Poirier JT;Rice CM
黄病毒对人类健康构成持续威胁。这些RNA病毒通过受感染的蚊子和蜱的叮咬传播，并定期引起疫情。为了鉴定黄病毒感染所需的宿主因子，我们进行了全基因组功能丧失CRISPR-Cas9筛选。基于这些结果，我们集中精力描述TMEM 41 B和VMP 1在病毒复制周期中的作用。我们对TMEM 41 B的机制研究表明，我们测试的黄病毒科家族的所有成员都需要TMEM 41 B。我们测试了另外12个病毒家族，发现冠状病毒科的SARS-CoV-2也需要TMEM 41 B进行感染。值得注意的是，东亚人群中近20%的单核苷酸多态性减少了黄病毒感染。基于我们的机制研究，我们提出TMEM 41 B被招募到黄病毒RNA复制复合物中以促进膜弯曲，这为病毒基因组复制创造了受保护的环境。Hoffmann等确定跨膜蛋白TMEM 41 B是黄病毒科病毒感染所必需的。TMEM 41 B的缺失减少了病毒RNA复制并增加了响应黄病毒感染的先天免疫激活。因此，TMEM 41 B是抗病毒治疗的潜在宿主靶标。
Flaviviruses pose a constant threat to human health. These RNA viruses are transmitted by the bite of infected mosquitoes and ticks and regularly cause outbreaks. To identify host factors required for flavivirus infection, we performed full-genome loss of function CRISPR-Cas9 screens. Based on these results, we focused our efforts on characterizing the roles that TMEM41B and VMP1 play in the virus replication cycle. Our mechanistic studies on TMEM41B revealed that all members of the Flaviviridae family that we tested require TMEM41B. We tested 12 additional virus families and found that SARS-CoV-2 of the Coronaviridae also required TMEM41B for infection. Remarkably, single nucleotide polymorphisms present at nearly 20% in East Asian populations reduce flavivirus infection. Based on our mechanistic studies, we propose that TMEM41B is recruited to flavivirus RNA replication complexes to facilitate membrane curvature, which creates a protected environment for viral genome replication. Hoffmann et al. determine that the transmembrane protein, TMEM41B, is required for infection by members of the Flaviviridae family of viruses. Loss of TMEM41B reduces viral RNA replication and increases innate immune activation in response to flavivirus infection. Thus, TMEM41B is a potential host target for antiviral therapeutics.
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