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"VACCINIA VIRUS ENCODED TYPE I INTERFERON (IFN) ANTAGONIST CAN EFFICIENTLY SUPPRESS IFN SIGNALING INDEPENDENTLY OF IFN BINDING"

by
Murugabaskar Balan
Biochemistry and Molecular Biology Program
B.Tech. 2003, Anna University, Tamilnadu, India




Thesis Advisor: Sergei Kotenko, Ph.D.
Associate Professor
Department of Biochemistry and Molecular Biology
University Hospital Cancer Center

Tuesday, July 27, 2010
MSB E-609b, 12:00 P.M.


Abstract

Interferons (IFNs) are cytokines that induce resistance to viral infection. Three types of IFNs induce antiviral state in cells by signaling through unique receptor heterodimers. One of the strategies employed by poxviruses to counteract the action of IFNs is the production of soluble IFN binding proteins that serve as IFN antagonists. These proteins bind IFNs and suppress IFN-induced signaling and biological activities. B18, a secreted glycoprotein from Vaccinia virus, can be found as a secreted or membrane bound form, and both forms can efficiently block type I IFNs. With the use of truncated B18 variants, we demonstrate that all three Ig-like domains of B18 are important for binding IFN- and neutralizing the transmembrane JAK-STAT (Janus Kinase Signal Transducers and activators of transcription) signaling of IFN-, however binding to the cell surface is mediated by the first N-terminal Ig-like domain. Moreover, we also found that cell surface binding of B18 is increased in cells after IFN treatment. In addition, we provide evidence that binding of B18 to the cell surface triggers phosphatases resulting in accelerated dephosphorylation of STAT1 and efficient inactivation of type I IFN-induced JAK-STAT signaling. Collectively, these findings reveal the novel functional role of the cell surface binding of B18 in suppressing type I IFN signaling by mechanisms distinct from type I IFN binding. This novel mechanism expands the set of viral strategies against type I IFNs.


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