In earlier studies we provided evidence that vaccinia virus (VACV) phosphorylation-activation of host cell signaling effectors is critical for subsequent viral replication. In this report, using mass spectrometry-based proteomics, we have identified 387 host cell proteins that co-immunoprecipitate with VACV in infected, permissive PM1.CCR5 human T cells. Among these, glomulin was distinguishable based on its known interaction with a tyrosine kinase receptor, c-Met, its ability to become tyrosine-phosphorylated, and its association with signaling effectors. siRNA knockdown of glomulin expression in PM1.CCR5 T cells reduces VACV infection. Glomulin interacts with the inactive, nonphosphorylated form of c-MET. We demonstrate that treatment of PM1.CCR5 T cells with a c-Met phosphorylation inhibitor leads to a significant reduction in VACV infectivity. Additionally, inhibition of phosphorylation of c-Met abrogates VACV-inducible phosphorylation of Erk 1/2 and IRS-2, signaling effectors identified as critical for VACV infection. These data identify glomulin as a permissivity factor for VACV infection and as a potential therapeutic target for inhibition of VACV infection.
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