biostudies-literatureHoffmann HHNational Institute of Allergy and Infectious DiseasesNIAID NIH HHSRobertson FoundationNCI NIH HHSNational Institutes of HealthNIHBoehringer Ingelheim FondsNIGMS NIH HHSBAWD Foundation133-148.e20https://www.ebi.ac.uk/biostudies/studies/S-EPMC7954666biostudies-literatureUnknown184(1)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.CellTMEM41B Is a Pan-flavivirus Host Factor.PMC7954666T32 GM007250R01 AI124690P30 CA008748P30 CA016087R01 CA213448R01AI124690MacDonald MRYi SSchneider WMJacobson EPoirier JTMiles LAHoffmann HHMcMullan LKRazooky BSchuster FRozen-Gagnon KRudin CMRice CMWu XfalseTMEM41B Is a Pan-flavivirus Host Factor.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.2021-01-01T00:00:00Z2021 Jan2024-11-13T06:25:46.668Z2021-03-18T08:36:38ZS-EPMC79546663333842110.1016/j.cell.2020.12.005