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


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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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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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).

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