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

Nature. 2010 Oct 14;467(7317):859-62.

Jun Arii,1,4 Hideo Goto,2 Tadahiro Suenaga,5 Masaaki Oyama,3 Hiroko Kozuka-Hata,3 Takahiko Imai,1 Atsuko Minowa,1 Hiroomi Akashi,4 Hisashi Arase,5,6, 7 Yoshihiro Kawaoka,2, 8, 9, 10 and Yasushi Kawaguchi1*

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 2. Division of Virology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo 108-8639, Japan 3. Medical Proteomics Laboratory, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo 108-8639, Japan 4. Department of Veterinary Microbiology, Graduate School of Agricultural and Life Science, The University of Tokyo, Bunkyo-ku, Tokyo 113-8657, Japan 5. Department of Immunochemistry, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan 6. WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan 7. Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Saitama 332-0012, Japan 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 9. Department of Pathobiological Sciences, University of Wisconsin-Madison, Madison, WI 53711, USA 10. ERATO Infection-Induced Host Responses Project, Saitama 332-0012, Japan

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 encephalitis. HSV-1 entry into host cells requires cellular receptors for both envelope glycoproteins B (gB) and D (gD). However, the gB receptors responsible for its broad host range in vitro and infection of critical targets in vivo 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 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, 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 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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