Nectin-4 mediates rubella virus entry in airway and placental cells

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.

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Publication Details

Journal
Nature
Published
2026-11-04
DOI
https://doi.org/10.1038/s41586-026-11248-2
Primary Topic
Virology and Viral Diseases
Type
article
Field-Weighted Citation Impact
0.00

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article

Nectin-4 mediates rubella virus entry in airway and placental cells

Misato Nagai, Masatoshi Kakizaki, Mayuko Nishi, Yoshio Mori et al.
Nature
Virology and Viral Diseases
article

Nectin-4 mediates rubella virus entry in airway and placental cells

Misato Nagai, Masatoshi Kakizaki, Mayuko Nishi, Yoshio Mori, Hideki Aizaki, Akihide Ryo, Hironori Hayashi, Yuichiro Nakatsu, Prof. Eiichi N. Kodama, Wataru Kamitani, Miyuki Kawase, Shuhei Taguwa, Yayoi Kimura, Satoshi Suzuki, Yoko Ino, Masanori Isogawa, Hirokazu Kaji, Kazutaka Murayama, Kazuya Shirato, Yoshiharu Matsuura, Tatsuki Takahashi, Takeshi Hori, Masafumi Sakata, Kento Fukano
article en

Abstract

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.

Nature
Tokyo Medical and Dental University (JP), Japan Agency for Marine-Earth Science and Technology (JP), Gunma University (JP), National Institute of Infectious Diseases (JP), National Institute of Health Sciences (JP), Japan Institute for Health Security (JP), Yokohama City University (JP), The University of Osaka (JP)
Japan Agency for Medical Research and Development, Research Center for Biomedical Engineering, Japan Society for the Promotion of Science
Good health and well-being
Openalex Percentile: Top 100%
Virology and Viral Diseases
DOIOpen Access PDFOpenAlex
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