{ "abstract": "Flaviviruses (genus Orthoflavivirus) are arthropod-borne viruses which cause approximately 400 million annual global infections in humans. Flavivirus infection requires cellular machinery to facilitate replication and spread. All known flaviviruses replicate in association with the host endoplasmic reticulum (ER), where genome replication is confined within virus-induced ER invaginations called viral replication organelles (vROs). Despite the central role of these structures during flavivirus infection, the mechanisms underlying vRO biogenesis remain undefined—particularly the membrane rearrangements required for their formation. In this work, we report a conserved role for a cellular ER remodeling protein, atlastin-2 (ATL2), in the organization of vROs within infected cells. Using confocal and electron microscopy, we show that ATL2 depletion leads to a reduction in vRO spatial distribution in flavivirus-infected cells. Changes in vRO distribution corresponded with a decrease in virus production and robust induction of innate immune responses. We also demonstrate that ATL2 accumulates in areas of vRO formation during flavivirus infection. Critically, mutational analysis showed that a tethering-competent but fusion-defective ATL2 mutant was sufficient to rescue DENV and ZIKV replication in ATL2-knockout cells. Finally, targeting of ATL2 activity using synthetic peptides significantly reduced DENV replication in both immortalized and human primary cells, suggesting a possible avenue for targeting host ER functions to limit flavivirus replication. Taken together, these results show that membrane tethering plays a critical and conserved role in flavivirus infection, functioning to organize membranes for vRO biogenesis and limit cellular immune activation. Importantly, we provide evidence that ATL2-mediated membrane organization can be targeted to inhibit viral replication.\n\nFlaviviruses reshape cell membranes to build replication sites, but how these membranes are organized remains unclear. This study shows that homotypic membrane tethering driven by the host endoplasmic reticulum protein atlastin-2 is essential for organizing these sites and supporting viral replication.", "abstract_shown": true, "affiliations": [ "Department of Microbiology and Immunology, School of Medicine, Emory University, Atlanta, Georgia, United States of America", "Center for Childhood Infections and Vaccines, Children’s Healthcare of Atlanta, Division of Infectious Diseases, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, United States of America", "Emory Vaccine Center, Emory University, Atlanta, Georgia, United States of America", "Leibniz Institute of Virology, Hamburg, Germany", "Centre Armand-Frappier Santé Biotechnologie, Institut National de la Recherche Scientifique, Laval, Quebec, Canada", "German Center for Infection Research, Hamburg-Borstel-Lübeck-Riems, Hamburg, Germany", "Centre for Structural Systems Biology (CSSB), Hamburg, Germany", "Faculty of Mathematics, Informatics and Natural Sciences, Department of Biology, University of Hamburg, Hamburg, Germany" ], "article_type": "Research Article", "arxiv": null, "author_total": 13, "authors": [ { "affs": [ 0 ], "name": "Jonathan Einterz Owen" }, { "affs": [ 1 ], "name": "Cheyanne Lynn Bemis" }, { "affs": [ 2 ], "name": "Qingyi Wang" }, { "affs": [ 3 ], "name": "Ambarish C. Varadan" }, { "affs": [ 4 ], "name": "Jacob W. Vander Velden" }, { "affs": [ 5 ], "name": "Laura Andačić" }, { "affs": [ 6 ], "name": "Olus Uyar" }, { "affs": [ 7 ], "name": "Mansi Gupta" }, { "name": "Christopher D. Scharer" }, { "name": "Laurent Chatel-Chaix" }, { "name": "Pietro Scaturro" }, { "name": "Mehul S. Suthar" }, { "name": "Christopher J. Neufeldt" } ], "bibtex": "https://research.draconitic.com/paper/apv16w4ej4j19.bib", "cited_by": 0, "doi": "10.1371/journal.pbio.3003556", "fulltext_url": "https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3003556", "id": "apv16w4ej4j19", "issns": [ "1545-7885" ], "landing_url": "https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3003556", "language": null, "licence": "CC-BY-4.0", "licence_label": "CC BY 4.0", "licence_source": "journal", "licence_url": "https://creativecommons.org/licenses/by/4.0/", "metadata_licence": null, "native_subjects": [ [ "openalex", "2739|Mosquito-borne diseases and control" ], [ "plos", "/Biology and life sciences/Biochemistry/Nucleic acids/RNA/RNA structure/RNA folding" ], [ "plos", "/Biology and life sciences/Cell biology/Cellular structures and organelles/Cell membranes" ], [ "plos", "/Biology and life sciences/Cell biology/Cellular structures and organelles/Cell membranes/Membrane fusion" ], [ "plos", "/Biology and life sciences/Immunology/Immunity/Immune activation" ], [ "plos", "/Biology and life sciences/Microbiology/Medical microbiology/Microbial pathogens/Viral pathogens/Flaviviruses" ], [ "plos", "/Biology and life sciences/Microbiology/Medical microbiology/Microbial pathogens/Viral pathogens/Flaviviruses/Dengue virus" ], [ "plos", "/Biology and life sciences/Microbiology/Virology/Viral replication" ], [ "plos", "/Biology and life sciences/Molecular biology/Macromolecular structure analysis/RNA structure/RNA folding" ], [ "plos", "/Biology and life sciences/Molecular biology/Molecular biology techniques/Transfection" ], [ "plos", "/Biology and life sciences/Organisms/Viruses/RNA viruses/Flaviviruses" ], [ "plos", "/Biology and life sciences/Organisms/Viruses/RNA viruses/Flaviviruses/Dengue virus" ], [ "plos", "/Biology and life sciences/Organisms/Viruses/Viral pathogens/Flaviviruses" ], [ "plos", "/Biology and life sciences/Organisms/Viruses/Viral pathogens/Flaviviruses/Dengue virus" ], [ "plos", "/Medicine and health sciences/Immunology/Immunity/Immune activation" ], [ "plos", "/Medicine and health sciences/Pathology and laboratory medicine/Pathogens/Microbial pathogens/Viral pathogens/Flaviviruses" ], [ "plos", "/Medicine and health sciences/Pathology and laboratory medicine/Pathogens/Microbial pathogens/Viral pathogens/Flaviviruses/Dengue virus" ], [ "plos", "/Research and analysis methods/Molecular biology techniques/Transfection" ] ], "openalex": "W7213257798", "pdf_url": "https://journals.plos.org/plosbiology/article/file?id=10.1371/journal.pbio.3003556&type=printable", "pmcid": null, "pmid": null, "published": "2026-09-15", "publisher": "Public Library of Science", "ris": "https://research.draconitic.com/paper/apv16w4ej4j19.ris", "sources": [ { "first_seen": "2026-10-30T12:17:49Z", "native_id": "10.1371/journal.pbio.3003556", "source": "plos", "url": "https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3003556" } ], "subjects": [ { "field": "biology", "origin": "plos:cell biology", "subfield": "cell-biology" }, { "field": "biology", "origin": "plos:immunology", "subfield": "immunology" }, { "field": "biology", "origin": "plos:microbiology", "subfield": "microbiology" } ], "title": "Atlastin-2-mediated endoplasmic reticulum membrane tethering is critical for flavivirus replication", "title_text": "Atlastin-2-mediated endoplasmic reticulum membrane tethering is critical for flavivirus replication", "type": "peer-reviewed", "updated_at": "2026-10-30T12:17:49Z", "url": "https://research.draconitic.com/paper/apv16w4ej4j19", "venue": "PLOS Biology", "versions": [] }