Journal
NATURE
Volume 467, Issue 7317, Pages 859-U129Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nature09420
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Funding
- Japan Initiative for Global Research Network on Infectious Diseases
- Founding Research Center for Emerging
- Ministry of Education, Science, Sports and Culture of Japan
- Ministry of Health of Japan
- Takeda Science Foundation
- ERATO (Japan Science and Technology Agency)
- Japan Society for the Promotion of Science
- Grants-in-Aid for Scientific Research [21580372] Funding Source: KAKEN
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Herpes simplex virus-1 (HSV-1), the prototype of the a-herpesvirus family, causes life-long infections in humans. Although generally associated with various mucocutaneous diseases, HSV-1 is also involved in lethal encephalitis(1). HSV-1 entry into host cells requires cellular receptors for both envelope glycoproteins B (gB) and D (gD)(2-4). However, the gB receptors responsible for its broad host range in vitro and infection of critical targets in vivo1 remain unknown. Here we show that non-muscle myosin heavy chain IIA (NMHC-IIA), a subunit of non-muscle myosin IIA (NM-IIA), functions as an HSV-1 entry receptor by interacting with gB. A cell line that is relatively resistant to HSV-1 infection(5) became highly susceptible to infection by this virus when NMHC-IIA was overexpressed. Antibody to NMHC-IIA blocked HSV-1 infection in naturally permissive target cells. Furthermore, knockdown of NMHC-IIA in the permissive cells inhibited HSV-1 infection as well as cell-cell fusion when gB, gD, gH and gL were coexpressed. Cell-surface expression of NMHC-IIA was markedly and rapidly induced during the initiation of HSV-1 entry. A specific inhibitor of myosin light chain kinase, which regulates NM-IIA by phosphorylation(6), reduced the redistribution of NMHC-IIA as well as HSV-1 infection in cell culture and in a murine model for herpes stromal keratitis. NMHC-IIA is ubiquitously expressed in various human tissues and cell types(7) and, therefore, is implicated as a functional gB receptor that mediates broad HSV-1 infectivity both in vitro and in vivo. The identification of NMHC-IIA as an HSV-1 entry receptor and the involvement of NM-IIA regulation in HSV-1 infection provide an insight into HSV-1 entry and identify new targets for antiviral drug development.
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