title: Glomulin: a permissivity factor for vaccinia virus infection.
abstract: 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.
authors.affiliation: Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada.
authors.forename: Ramtin
authors.initials: R
authors.lastname: Rahbar
authors.forename: Erin
authors.initials: E
authors.lastname: Rogers
authors.forename: Thomas
authors.initials: T
authors.lastname: Murooka
authors.forename: Thomas
authors.initials: T
authors.lastname: Kislinger
authors.forename: Eleanor N
authors.initials: EN
authors.lastname: Fish
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D020868:Gene Silencing; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology; D040901:Proteomics / Q000379:methods; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors; D013449:Sulfonamides / Q000494:pharmacology; D014443:Tyrosine / Q000378:metabolism; D014616:Vaccinia virus / Q000378:metabolism*
chemical_list: C478479:((3Z)-N-(3-chlorophenyl)-3-((3,5-dimethyl-4-((4-methylpiperazin-1-yl)carbonyl)-1H-pyrrol-2-yl)methylene)-N-methyl-2-oxo-2,3-dihydro-1H-indole-5-sulfonamide); D048868:Adaptor Proteins, Signal Transducing; C103024:GLMN protein, human; D007211:Indoles; D010879:Piperazines; D013449:Sulfonamides; D014443:Tyrosine; D019859:Proto-Oncogene Proteins c-met; D048052:Mitogen-Activated Protein Kinase 3