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Non-muscle myosin IIA is a functional entry receptor for herpes simplex virus-1

Nature volume 467, pages 859–862 (2010)Cite this article

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Abstract

Herpes simplex virus-1 (HSV-1), the prototype of the α-herpesvirus family, causes life-long infections in humans. Although generally associated with various mucocutaneous diseases, HSV-1 is also involved in lethal encephalitis1. HSV-1 entry into host cells requires cellular receptors for both envelope glycoproteins B (gB) and D (gD)2,3,4. 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 infection5 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 phosphorylation6, 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 types7 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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Figure 1: NMHC-IIA associates with HSV-1 gB and mediates HSV-1 infection.
Figure 2: Endogenous NMHC-IIA mediates HSV-1 infection and cell–cell fusion.
Figure 3: Cell-surface expression of NMHC-IIA is upregulated after viral adsorption at 4 °C, followed by a temperature shift to 37 °C.
Figure 4: ML-7 inhibits HSV-1 infection in vitro and in vivo.

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Acknowledgements

We thank P. G. Spear, L. W. Enquist, Y. Matsuura, N. Mizushima, S. Sugano, R. Adelstein, T. Ichimura, K. Araki-Sasaki, Y. Mori and M. Takahashi for providing reagents, S. Koyama for technical assistance and K. Wells and S. Watson for critical reading of this manuscript. This study was supported by Grants-in-aid for Scientific Research, Grants-in-aid for Scientific Research in Priority Areas, Grants-in-aid for Specially Promoted Research, and contract research funds for the Program of Japan Initiative for Global Research Network on Infectious Diseases and the Program of Founding Research Center for Emerging and Reemerging Infectious Diseases from the Ministry of Education, Science, Sports and Culture of Japan, by Grants-in-aid from the Ministry of Health of Japan, by grants from the Takeda Science Foundation, and by ERATO (Japan Science and Technology Agency). J.A. was supported by research fellowships from the Japan Society for the Promotion of Science by Young Scientists.

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Authors and Affiliations

  1. Division of Viral Infection, Department of Infectious Disease Control, International Research Center for Infectious Diseases, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo 108-8639, Japan,

    Jun Arii, Takahiko Imai, Atsuko Minowa & Yasushi Kawaguchi

  2. Department of Veterinary Microbiology, Graduate School of Agricultural and Life Science, The University of Tokyo, Bunkyo-ku, Tokyo 113-8657, Japan,

    Jun Arii & Hiroomi Akashi

  3. Division of Virology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo 108-8639, Japan,

    Hideo Goto & Yoshihiro Kawaoka

  4. Department of Immunochemistry, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan,

    Tadahiro Suenaga & Hisashi Arase

  5. Medical Proteomics Laboratory, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo 108-8639, Japan ,

    Masaaki Oyama & Hiroko Kozuka-Hata

  6. WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan ,

    Hisashi Arase

  7. Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Saitama 332-0012, Japan ,

    Hisashi Arase

  8. Department of Special Pathogens, International Research Center for Infectious Diseases, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo 108-8639, Japan,

    Yoshihiro Kawaoka

  9. Department of Pathobiological Sciences, University of Wisconsin-Madison, Madison, 53711, Wisconsin, USA

    Yoshihiro Kawaoka

  10. ERATO Infection-Induced Host Responses Project, Saitama 332-0012, Japan ,

    Yoshihiro Kawaoka

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  1. Jun Arii
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Contributions

Y. Kawaguchi and J.A. designed the experiments; J.A., H.G., T.S., M.O., H.K.-H., T.I. and A.M. performed the experiments; Y. Kawaguchi, J.A., H. Akashi, H. Arase and Y. Kawaoka analysed and interpreted the data; Y. Kawaguchi and J.A. wrote the manuscript with the aid of Y. Kawaoka.

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Correspondence to Yasushi Kawaguchi.

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Arii, J., Goto, H., Suenaga, T. et al. Non-muscle myosin IIA is a functional entry receptor for herpes simplex virus-1. Nature 467, 859–862 (2010). https://doi.org/10.1038/nature09420

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