Identification of Nectin-4 as a rubella virus entry receptor mediating viral shedding and congenital transmission

Identification of Nectin-4 as a rubella virus entry receptor mediating viral shedding and congenital transmission | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Biological Sciences - Article Identification of Nectin-4 as a rubella virus entry receptor mediating viral shedding and congenital transmission Yoshio Mori, Masafumi Sakata, Yuichiro Nakatsu, Takeshi Hori, and 15 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7626754/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract Rubella virus (RuV) causes rubella and, when acquired during pregnancy, congenital rubella syndrome (CRS). Despite its clinical significance, the cellular entry mechanism of RuV remains poorly characterized owing to limited knowledge of host receptors, hampering pathogenesis studies and therapeutic development. Here, we identify Nectin-4 as a functional RuV entry receptor through proximity biotin labeling-based proteomics coupled with CRISPR/Cas9 validation. Notably, Nectin-4 is shared with measles virus, revealing convergent evolution in viral entry despite the different viral families. Nectin-4 directly interacts with the RuV envelope glycoproteins through its ectodomain, facilitating receptor-mediated endocytosis following initial calcium-dependent viral attachment. In polarized respiratory epithelial cells, Nectin-4 mediates basolateral viral entry and subsequent apical release of progeny virions, enabling efficient respiratory transmission. Using human placental organoid models, we demonstrate that syncytiotrophoblasts serve as primary targets for transplacental RuV infection, with viral entry significantly inhibited by Nectin-4 blockade. These findings establish Nectin-4 as critical for both horizontal respiratory transmission and vertical maternal–fetal transmission of RuV. Our results provide fundamental insights into RuV pathogenesis and identify Nectin-4 as a promising therapeutic target for CRS. Importantly, the discovery of shared receptor utilization between RuV and measles virus opens new avenues for integrated elimination strategies targeting both pathogens. Biological sciences/Microbiology/Virology/Viral transmission Biological sciences/Biological techniques/Microbiology techniques Full Text Additional Declarations There is NO Competing Interest. Supplementary Files 2SupplementalTables.xlsx Datasets 1-4 3SupFig.pdf Supprementary figures Cite Share Download PDF Status: Under Review Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7626754","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Biological Sciences - Article","associatedPublications":[],"authors":[{"id":543539042,"identity":"296034a8-d03b-4cd4-8b4e-821239350cfc","order_by":0,"name":"Yoshio 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Despite its clinical significance, the cellular entry mechanism of RuV remains poorly characterized owing to limited knowledge of host receptors, hampering pathogenesis studies and therapeutic development. Here, we identify Nectin-4 as a functional RuV entry receptor through proximity biotin labeling-based proteomics coupled with CRISPR/Cas9 validation. Notably, Nectin-4 is shared with measles virus, revealing convergent evolution in viral entry despite the different viral families. Nectin-4 directly interacts with the RuV envelope glycoproteins through its ectodomain, facilitating receptor-mediated endocytosis following initial calcium-dependent viral attachment. In polarized respiratory epithelial cells, Nectin-4 mediates basolateral viral entry and subsequent apical release of progeny virions, enabling efficient respiratory transmission. Using human placental organoid models, we demonstrate that syncytiotrophoblasts serve as primary targets for transplacental RuV infection, with viral entry significantly inhibited by Nectin-4 blockade. These findings establish Nectin-4 as critical for both horizontal respiratory transmission and vertical maternal–fetal transmission of RuV. Our results provide fundamental insights into RuV pathogenesis and identify Nectin-4 as a promising therapeutic target for CRS. 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