Modulation of T-cell receptor signal transduction by herpesvirus signaling adaptor protein.
Because of its central regulatory role, T-cell receptor (TCR) signal transduction is a common target of viruses. We report here the identification of a small signaling protein, ORF5, of the T-lymphotropic tumor virus herpesvirus saimiri (HVS). ORF5 is predicted to contain 89 to 91 amino acids with an amino-terminal myristoylation site and six SH2 binding motifs, showing structural similarity to cellular LAT (linker for activation of T cells). Sequence analysis showed that, despite extensive sequence variation, the myristoylation site and SH2 binding motifs were completely conserved among 13 different ORF5 isolates. Upon TCR stimulation, ORF5 was efficiently tyrosine phosphorylated and subsequently interacted with cellular SH2-containing signaling proteins Lck, Fyn, SLP-76, and p85 through its tyrosine residues. ORF5 expression resulted in the marked augmentation of TCR signal transduction activity, evidenced by increased cellular tyrosine phosphorylation, intracellular calcium mobilization, CD69 surface expression, interleukin-2 production, and activation of the NF-AT, NF-kappa B, and AP-1 transcription factors. Despite its structural similarity to cellular LAT, however, ORF5 could only partially substitute for LAT function in TCR signal transduction. These results demonstrate that HVS utilizes a novel signaling protein, ORF5, to activate TCR signal transduction. This activation probably facilitates viral gene expression and, thereby, persistent infection.
Lee
Sun-Hwa
SH
Department o fMicrobiology and Molecular Genetics and Tumor Virology Division, New England Regional Primate Research Center, Harvard Medical School, Southborough, MA 01772-9102, USA.
Chung
Young-Hwa
YH
Cho
Nam-Hyuk
NH
Gwack
Yousang
Y
Feng
Pinghui
P
Jung
Jae U
JU
D000483:Alleles; D000595:Amino Acid Sequence; D001665:Binding Sites; D002460:Cell Line; D005814:Genes, Viral; D006567:Herpesvirus 2, Saimiriine / Q000235:genetics / Q000472:pathogenicity* / Q000502:physiology; D006801:Humans; D019169:Jurkat Cells; D021962:Membrane Microdomains / Q000821:virology; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology* / Q000821:virology*; D014443:Tyrosine / Q000737:chemistry; D014764:Viral Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D018909:src Homology Domains; D019061:src-Family Kinases / Q000378:metabolism
D011948:Receptors, Antigen, T-Cell; D014764:Viral Proteins; D014443:Tyrosine; D019061:src-Family Kinases