Cell-type-specific tyrosine phosphorylation of the herpes simplex virus tegument protein VP11/12 encoded by gene UL46.
Cytotoxic T lymphocytes (CTL) and natural killer (NK) cells play key roles in limiting herpesvirus infections; consequently, many herpesviruses, including herpes simplex virus (HSV), have evolved diverse strategies to evade and/or disarm these killer lymphocytes. Previous studies have shown that CTL and NK cells are functionally inactivated following contact with HSV-infected fibroblasts. During studies of the mechanisms involved, we discovered that HSV-inactivated NK-92 NK cells and Jurkat T cells contain a strikingly prominent, novel, ca. 90-kDa tyrosine-phosphorylated protein that we identified as the HSV tegument protein VP11/12. Inasmuch as VP11/12 produced in fibroblasts and epithelial cells is not obviously tyrosine phosphorylated, these data suggested that VP11/12 serves as the substrate of a cell-type-specific protein tyrosine kinase. Consistent with this hypothesis, VP11/12 was also tyrosine phosphorylated in B lymphocytes, and this modification was severely reduced in Jurkat T cells lacking the lymphocyte-specific Src family kinase Lck. These findings demonstrate that HSV tegument proteins can be differentially modified depending on the cell type infected. Our data also raise the possibility that VP11/12 may modulate one or more lymphocyte-specific signaling pathways or serve another lymphocyte-specific function. However, HSV type 1 mutants lacking the UL46 gene retained the ability to block signaling through the T-cell receptor in Jurkat cells and remained competent to functionally inactivate the NK-92 NK cell line, indicating that VP11/12 is not essential for lymphocyte inactivation. Further studies are therefore required to determine the biological function of tyrosine-phosphorylated VP11/12.
Zahariadis
George
G
Alberta Institute for Viral Immunology, Department of Medical Microbiology and Immunology, University of Alberta, 632 Heritage Medical Research Center, Edmonton, Alberta T6G 2S2, Canada.
Wagner
Melany J
MJ
Doepker
Rosalyn C
RC
Maciejko
Jessica M
JM
Crider
Carly M
CM
Jerome
Keith R
KR
Smiley
James R
JR
D000956:Antigens, Viral / Q000378:metabolism*; D015139:Blotting, Southern; D015153:Blotting, Western; D017931:DNA Primers / Q000235:genetics; D006801:Humans; D019169:Jurkat Cells; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D013058:Mass Spectrometry; D010766:Phosphorylation; D010957:Plasmids / Q000235:genetics; D015398:Signal Transduction / Q000276:immunology*; D014443:Tyrosine / Q000378:metabolism*; D014764:Viral Proteins / Q000378:metabolism*
D000956:Antigens, Viral; D017931:DNA Primers; C414831:UL46 protein, Human herpesvirus 1; D014764:Viral Proteins; D014443:Tyrosine