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

Plum Island Animal Disease Center, Agricultural Research Service, U.S. Department of Agriculture, Greenport, NY 11944, USA.
Virology (Impact Factor: 3.32). 03/2011; 412(1):68-74. DOI: 10.1016/j.virol.2010.12.060
Source: PubMed


Here we show that IQGAP1, a cellular protein that plays a pivotal role as a regulator of the cytoskeleton interacts with Classical Swine Fever Virus (CSFV) Core protein. Sequence analyses identified 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 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.

Download full-text


Available from: Guillermo Risatti
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: IQGAP proteins have been identified in a wide spectrum of organisms, ranging from yeast to humans. The most extensively studied family member is the ubiquitously expressed scaffold protein IQGAP1, which participates in multiple essential aspects of mammalian biology. IQGAP1 mediates these effects by binding to and regulating the function of numerous interacting proteins. Over ninety proteins have been reported to associate with IQGAP1, either directly or as part of a larger complex. In this review, we summarise those IQGAP1 binding partners that have been identified in the last five years. The molecular mechanisms by which these interactions contribute to the functions of receptors and their signalling cascades, small GTPase function, cytoskeletal dynamics, neuronal regulation and intracellular trafficking are evaluated. The evidence that has accumulated recently validates the role of IQGAP1 as a scaffold protein and expands the repertoire of cellular activities in which it participates.
    Full-text · Article · Dec 2011 · Cellular Signalling
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Classical swine fever virus (CSFV) is the causative agent of classical swine fever (CSF), a highly contagious disease of pigs. There are numerous CSFV strains that differ in virulence, resulting in clinical disease with different degrees of severity. Low-virulent and moderately virulent isolates cause a mild and often chronic disease, while highly virulent isolates cause an acute and mostly lethal hemorrhagic fever. The live attenuated vaccine strain GPE− was produced by multiple passages of the virulent ALD strain in cells of swine, bovine, and guinea pig origin. With the aim of identifying the determinants responsible for the attenuation, the GPE− vaccine virus was readapted to pigs by serial passages of infected tonsil homogenates until prolonged viremia and typical signs of CSF were observed. The GPE−/P-11 virus isolated from the tonsils after the 11th passage in vivo had acquired 3 amino acid substitutions in E2 (T830A) and NS4B (V2475A and A2563V) compared with the virus before passages. Experimental infection of pigs with the mutants reconstructed by reverse genetics confirmed that these amino acid substitutions were responsible for the acquisition of pathogenicity. Studies in vitro indicated that the substitution in E2 influenced virus spreading and that the changes in NS4B enhanced the viral RNA replication. In conclusion, the present study identified residues in E2 and NS4B of CSFV that can act synergistically to influence virus replication efficiency in vitro and pathogenicity in pigs.
    Full-text · Article · Jun 2012 · Journal of Virology
  • [Show abstract] [Hide abstract]
    ABSTRACT: Heme oxygenase 1 (HO-1) is an inducible enzyme that exerts potent antioxidant and anti-inflammatory effects, which also plays a critical role in host defenses against microbial, and particularly viral, infections. In our previous study, up-regulation of HO-1 was observed in peripheral blood leukocytes (PBLs) by genomic expression profiling, following infection of pigs with virulent classical swine fever virus (CSFV), the causative agent of a highly contagious disease threatening global pig industry (Shi et al., 2009). To study the potential involvement of HO-1 in CSFV proliferation, the role of its down-regulation in CSFV-infected PK-15 cells was further investigated. Results showed that infection with virulent CSFV strain Shimen significantly up-regulated the expression of HO-1 and that its down-regulation by small interfering RNA (siRNA) could inhibit CSFV proliferation as measured by genomic replication and production of infectious virus. The study revealed the involvement of HO-1 in CSFV proliferation, indicating that HO-1 is a potential target for inhibition of CSFV replication.
    No preview · Article · Jan 2013 · Virus Research
Show more