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Journal of Virology, January 2009, p. 250-261, Vol. 83, No. 1
0022-538X/09/$08.00+0     doi:10.1128/JVI.01451-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Herpes Simplex Virus 1 Protein Kinase Us3 Phosphorylates Viral Envelope Glycoprotein B and Regulates Its Expression on the Cell Surface{triangledown}

Akihisa Kato,1,{dagger} Jun Arii,1,2,{dagger} Ikuo Shiratori,3,{ddagger} Hiroomi Akashi,2 Hisashi Arase,3,4 and Yasushi Kawaguchi1*

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 108-8639,1 Department of Veterinary Microbiology, Graduate School of Agricultural and Life Science, The University of Tokyo, Bunkyo-ku, Tokyo 113-8657,2 Laboratory of Immunochemistry, Research Institute for Microbial Diseases and WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871,3 SORT, JST, Saitama 332-0012, Japan4

Received 11 July 2008/ Accepted 15 October 2008

Us3 is a serine-threonine protein kinase encoded by herpes simplex virus 1 (HSV-1). As reported here, we attempted to identify the previously unreported physiological substrate of Us3 in HSV-1-infected cells. Our results were as follows. (i) Bioinformatics analysis predicted two putative Us3 phosphorylation sites in the viral envelope glycoprotein B (gB) at codons 557 to 562 (RRVSAR) and codons 884 to 889 (RRNTNY). (ii) In in vitro kinase assays, the threonine residue at position 887 (Thr-887) in the gB domain was specifically phosphorylated by Us3, while the serine residue at position 560 was not. (iii) The phosphorylation of gB Thr-887 in Vero cells infected with wild-type HSV-1 was specifically detected using an antibody that recognized phosphorylated serine or threonine residues with arginine at the –3 and –2 positions. (iv) The phosphorylation of gB Thr-887 in infected cells was dependent on the kinase activity of Us3. (v) The replacement of Thr-887 with alanine markedly upregulated the cell surface expression of gB in infected cells, whereas replacement with aspartic acid, which sometimes mimics constitutive phosphorylation, restored the wild-type phenotype. The upregulation of gB expression on the cell surface also was observed in cells infected with a recombinant HSV-1 encoding catalytically inactive Us3. These results supported the hypothesis that Us3 phosphorylates gB and downregulates the cell surface expression of gB in HSV-1-infected cells.

* Corresponding author. Mailing address: Division of Viral Infection, Department of Infectious Disease Control, International Research Center for Infectious Diseases, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan. Phone: 81-3-6409-2070. Fax: 81-3-6409-2072. E-mail: ykawagu{at}ims.u-tokyo.ac.jp

{triangledown} Published ahead of print on 22 October 2008.

{dagger} A.K. and J.A. contributed equally to this work.

{ddagger} Present address: Research Institute for Biological Sciences, Tokyo University of Science, 2669 Yamazaki, Noda, Chiba 278-0022, Japan.

Journal of Virology, January 2009, p. 250-261, Vol. 83, No. 1
0022-538X/09/$08.00+0     doi:10.1128/JVI.01451-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



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