The abundant HSV-1 tegument protein VP11/12 encoded by gene UL46 is essential for induction of the PI3K/Akt-signaling pathway during infection. VP11/12 utilizes tyrosine-based motifs within its C-terminal region to bind the SH2 domains of Src family kinases, the p85 subunit of PI3 Kinase and Grb2, and the PTB domain of Shc. We previously proposed that the interaction with SFKs and p85 is used to gain control over the PI3K/Akt signaling pathway. We tested this model by evaluating the effects of mutations that eliminate each of these interactions on the ability of HSV-1 to activate Akt. Inhibiting the interaction of VP11/12 with SFKs, p85 and Grb2 reduced Akt activation, while inhibiting the interaction with Shc had little effect. Overall these data support the suggestion that VP11/12 stimulates the PI3K/Akt pathway by mimicking an activated growth factor receptor.
Previous studies have shown that HSV-1 infection of lymphocytes induces the tyrosine phosphorylation of several proteins that might correspond to viral or host proteins. VP11/12, a viral tegument protein, is the major HSV-induced tyrosine phosphorylated protein identified thus far. In this report, we demonstrated that the cellular adaptor proteins Dok-2 and Dok-1 are tyrosine phosphorylated upon HSV-1 infection. In addition, HSV-1 induced the selective degradation of Dok-2. Finally, we provide evidence that Dok-2 interacts with VP11/12, and that HSV-induced tyrosine phosphorylation and degradation of Dok-2 require VP11/12. Inactivation of either the Src Family Kinases binding motifs or the SHC binding motif of VP11/12 eliminated the interaction of Dok-2 with VP11/12. Elimination of the binding of Dok-2 to VP11/12 prevented Dok-2 phosphorylation and degradation. We propose that HSV-induced Dok phosphorylation and Dok-2 degradation is an immune evasion mechanism to inactivate T cells that might play an important role in HSV pathogenesis.
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