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Dual roles for the ER Membrane Protein Complex in Flavivirus Infection: Viral Entry and Protein Biogenesis

dc.contributor.authorBarrows, Nicholas J.
dc.contributor.authorAnglero-Rodriguez, Yesseinia
dc.contributor.authorKim, Byungil
dc.contributor.authorJamison, Sharon F.
dc.contributor.authorLe Sommer, Caroline
dc.contributor.authorMcGee, Charles E.
dc.contributor.authorPearson, James L.
dc.contributor.authorDimopoulos, George
dc.contributor.authorAscano, Manuel
dc.contributor.authorBradrick, Shelton S.
dc.contributor.authorGarcia-Blanco, Mariano A.
dc.identifier.citationBarrows, Nicholas J., Anglero-Rodriguez, Yessseinia, Kim, Byungil, Jamison, Sharon, Le Sommer, Caroline, McGee, Charles E., Pearson, James L., Dimopoulos, George, Ascano, Manuel, Bradrick, Shelton S., Garcia-Blanco, Mariano A., 2019, Dual roles for the ER membrane protein complex in flavivirus infection: viral entry and protein biogenesis, Scientific Reports 9711, 9, 1,en_US
dc.description.abstractHundreds of cellular host factors are required to support dengue virus infection, but their identity and roles are incompletely characterized. Here, we identify human host dependency factors required for efficient dengue virus-2 (DENV2) infection of human cells. We focused on two, TTC35 and TMEM111, which we previously demonstrated to be required for yellow fever virus (YFV) infection and others subsequently showed were also required by other flaviviruses. These proteins are components of the human endoplasmic reticulum membrane protein complex (EMC), which has roles in ER-associated protein biogenesis and lipid metabolism. We report that DENV, YFV and Zika virus (ZIKV) infections were strikingly inhibited, while West Nile virus infection was unchanged, in cells that lack EMC subunit 4. Furthermore, targeted depletion of EMC subunits in live mosquitoes significantly reduced DENV2 propagation in vivo. Using a novel uncoating assay, which measures interactions between host RNA-binding proteins and incoming viral RNA, we show that EMC is required at or prior to virus uncoating. Importantly, we uncovered a second and important role for the EMC. The complex is required for viral protein accumulation in a cell line harboring a ZIKV replicon, indicating that EMC participates in the complex process of viral protein biogenesis.en_US
dc.description.sponsorshipWe thank our colleagues from the Bradrick and Garcia-Blanco laboratory, University of Texas Medical Branch and Duke University for their support. We thank Drs. Xuping Xie and Pei-Yong Shi for the ZIKV replicon cell line, DENV2-RLuc virus and very helpful scientific input. This work was supported by NIH grants R01-AI089526 and R01-AI101431 (MAG-B), 1R35GM119569 (M.A.), CTSA award No. UL1TR000445 from the National Center for Advancing Translational Sciences (B.K. and M.A.), startup funds from the University of Texas Medical Branch, a University of Texas System Texas STARs Award (MAG-B). BSL3 experiments were performed in the Duke Regional Biocontainment Laboratory (RBL) which received partial support for construction from the National Institutes of Health, National Institute of Allergy and Infectious Diseases (UC6-AI058607). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. During review of our manuscript a paper from Tai and colleagues, which was published in Cell Reports (PMID 31067454), reached similar conclusions as we had.en_US
dc.rightsThis is an open access article distributed under the terms of the Creative Commons CC BY license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. You are not required to obtain permission to reuse this article. To request permission for a type of use not listed, please contact Springer Nature
dc.subjectyellow-fever virusen_US
dc.subjectdengue virusen_US
dc.subjectZika virusen_US
dc.subjecthost factorsen_US
dc.titleDual roles for the ER Membrane Protein Complex in Flavivirus Infection: Viral Entry and Protein Biogenesisen_US

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