Interaction between core protein of classical swine fever virus with cellular IQGAP1 proetin appears essential for virulence in swine

Authors: Gladue, Douglas; Holinka-Patterson, Lauren; FERNANDEZ-SAINZ, IGNACIO - Oak Ridge Institute For Science And Education (ORISE); PRARAT, MELANIE - Former ARS Employee; O'DONNELL, VIVIAN - University Of Connecticut; VEPKHVADZE, NINO - Oak Ridge Institute For Science And Education (ORISE); LU, ZHIQIANG - Us Deparment Of Homeland Security; RISATTI, GUILLERMO - University Of Connecticut; Borca, Manuel

Submitted to: Virology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/30/2010
Publication Date: 3/30/2011
Citation: Gladue, D.P., Holinka-Patterson, L.G., Fernandez-Sainz, I., Prarat, M.V., O'Donnell, V.K., Vepkhvadze, N., Lu, Z., Risatti, G.R., Borca, M.V. 2011. Interaction between core protein of classical swine fever virus with cellular IQGAP1 proetin appears essential for virulence in swine. Virology. 412:68-74.

Interpretive Summary: Core is one of the four structural proteins of Classical Swine Fever Virus (CSFV) a virus causing a severe disease in swine. Knowledge of Core function is very limited. Recently, we report the identification of two swine proteins that interact with CSFV Core during the virus infection. We showed that that interaction was critical in the process of the disease produced by the virus in pigs. In this new report we extended those studies identifying a new swine protein, named IQGAP, that specifically interact with the virus Core protein. The sites of the Core protein which actually interact with this host protein were identified. CSFV harboring alteration of regions in Core that interact with IQGAP resulted completely attenuated in swine. Therefore CSFV Core protein specifically interacts with at least three swine host protein during the cycle of virus replication and this interaction appears to be critical in the mechanism of virus virulence. These results will be useful in vaccine development against this important disease.

Technical Abstract: Here we show that IQGAP1, a cellular protein that plays a pivotal role as a regulator of the cytoskeleton affecting cell adhesion, polarization and migration, interacts with Classical Swine Fever Virus (CSFV) Core protein. Sequence analyses identified a defined set of residues within CSFV Core protein (designated as areas I, II, III and IV) that maintain homology to regions within the matrix protein of Moloney Murine Leukemia Virus (MMLV) that mediate binding to IQGAP1 [EMBO J, 2006 25:2155]. Alanine-substitution within the Core regions I, II, III and IV identified residues that specifically mediate the Core-IQGAP1 interaction. Recombinant CSFV viruses harboring alanine substitutions at residues ^207 ATI ^209 (I), ^210 VVE ^212 (II), ^213 GVK ^215 (III), or ^232 GLYHN ^236 (IV) have defective growth in primary swine macrophage cultures. In vivo, substitutions of residues in areas I and III yielded viruses that were completely attenuated in swine. These data shows that the interaction of Core with an integral component of cytoskeletal regulation plays a role in the CSFV cycle.