Identification of transforming genes of subgroup A and C strains of Herpesvirus saimiri.

Jung, Jae U.; Trimble, John J.; King, Norval W.; Biesinger, Brigitte; Fleckenstein, Bernhard; Desrosiers, Ronald C.

doi:10.1073/pnas.88.16.7051

Cited by 127 publications

(108 citation statements)

References 24 publications

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“…Based on sequence conservation, both the myristoylation and SH2 binding motifs are predicted to have important roles in ORF5 function. Since HVS subgroup C strain 488 has been well characterized (28), the ORF5 protein from this strain was selected for the rest of study. Amino-terminal myristoylation and lipid raft localization of ORF5.…”

Section: Resultsmentioning

confidence: 99%

“…These are the STP oncoprotein and the Tip signaling protein. Neither of these proteins is required for viral replication, but they are required for in vitro T-cell immortalization and in vivo lymphoma induction (28). Our study has added ORF5 to this list of divergent viral proteins.…”

Section: Discussionmentioning

confidence: 99%

“…Our study has added ORF5 to this list of divergent viral proteins. Interestingly, all three viral proteins play important roles in the deregulation of cellular signal transduction: STP activates Ras and TRAF signal transduction (26), Tip deregulates Lck signal transduction (28), and ORF5 enhances TCR signal transduction. This unusually high diversity between HVS subgroups reflects some unknown, powerful biological selection process that has been acting preferentially on these viral signaling proteins.…”

Section: Discussionmentioning

confidence: 99%

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Modulation of T-Cell Receptor Signal Transduction by Herpesvirus Signaling Adaptor Protein

Lee

Chung

Cho

et al. 2004

Molecular and Cellular Biology

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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-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.Upon engagement of the T-cell antigen receptor (TCR), many cellular proteins, including TCR subunits, adaptor proteins, and other effector molecules, are phosphorylated and subsequently are involved in the formation of molecular complexes at the site of contact with the antigen-presenting cells (33, 51, 54) The earliest signaling event following TCR engagement is the sequential activation of the non-receptor protein tyrosine kinases (PTKs) of the Src and Syk families. Activated Src family PTKs, Lck and Fyn, in T cells subsequently phosphorylate tyrosine residues within a consensus sequence termed the immunoreceptor tyrosine-based activation motif in the cytosolic tails of the TCR subunits. The phosphorylated immunoreceptor tyrosine-based activation motifs of TCR in turn recruit the Syk family PTKs ZAP70 and Syk through their Src homology 2 (SH2) domains (33). Together with Lck and Fyn, the ZAP70 and Syk kinases then promote the phosphorylation of many intracellular signaling molecules, including phospholipase C-␥1 (PLC-␥1), Cbl, Vav, LAT (linker for activation of T cells) and SLP-76 (SH2-containing leukocyte protein-76) (12,25,41,45,46,53). Phosphorylation of these cellular signaling molecules ultimately induces various cellular events such as cytoskeletal alteration, intracellular Ca ϩϩ influx, transcription factor activation, and cytokine/chemokine production (4,20,38,43,59).Two adaptor proteins, LAT and SLP-76, have been shown to be critical for the optimal activation of T cells and to function in linking proximal signaling events to distal downstream signaling ac...

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Modulation of T-Cell Receptor Signal Transduction by Herpesvirus Signaling Adaptor Protein

Lee

Chung

Cho

et al. 2004

Molecular and Cellular Biology

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“…14,16 The transformation-associated genes, tyrosine kinase-interacting protein (tip) and saimiri transformation-associated protein of subgroup C (stpC) are located at the left end of the L-DNA. 17,18 They are translated from a single bicistronic mRNA, and their transcription can be induced by T-cell activation. 19 Although these genes are dispensable for virus replication, their deletion abolishes the transformation capacity of HVS C488.…”

Section: Introductionmentioning

confidence: 99%

Rhadinovirus vector-derived human telomerase reverse transcriptase expression in primary T cells

2010

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The rhadinovirus herpesvirus saimiri (HVS) as a gene delivery vector allows large DNA insertions and long-termed gene expression. In the case of T-cell transduction, such vectors use the viral transformation-associated genes of HVS C488 for T-cell amplification. In this report, we investigated whether the gene for the catalytic telomerase subunit human telomerase reverse transcriptase (hTERT) can substitute for the transformation-associated genes in rhadinoviral T-cell transduction and amplification. By using virus mutants generated by en passant mutagenesis from bacterial artificial chromosomes, we observed a very early and functional transgene expression even by virus mutants without transformation-associated genes. The markers of T-cell transformation by HVS, namely CD2 hyperreactivity, overexpression of interleukin-26, and of the tyrosine kinase Lyn could neither be induced nor enhanced by ectopic hTERT expression. When the viral transformation-associated genes were replaced by the hTERT gene, it was not sufficient for growth transformation, although hTERT was efficiently transduced and functionally expressed by the rhadinovirus vector. Thus, the transformation-associated proteins StpC and Tip are responsible for the T-cell phenotype after transduction by HVS and, additionally, modulate telomerase activity independently of hTERT expression.

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“…In more recent times the suggestion of collagen-like molecules in other species has emerged, with (Gly-Xaa-Yaa) n repeating sequences present in a few fungi, 20 in viruses, 21 and in phage. 22 Most interesting, however, are the numerous collagen-like structures that are being identified in bacteria and in the emerging, large numbers of bacterial genomes.…”

Section: Recombinant Bacterial Collagen: An Emerging Systemmentioning

confidence: 99%

Bioengineered collagens

2014

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Identification of transforming genes of subgroup A and C strains of Herpesvirus saimiri.

Cited by 127 publications

References 24 publications

Modulation of T-Cell Receptor Signal Transduction by Herpesvirus Signaling Adaptor Protein

Modulation of T-Cell Receptor Signal Transduction by Herpesvirus Signaling Adaptor Protein

Rhadinovirus vector-derived human telomerase reverse transcriptase expression in primary T cells

Bioengineered collagens

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