Type I interferons (IFN) are the principal antiviral cytokines and function directly on target cells by blocking virus replication. IFN signal transduction produces a transcriptional complex, ISGF3, that is composed of a DNA binding subunit in association with two proteins from the signal transducer and activator of transcription (STAT) family, STAT1 and STAT2. ISGF3 is the main effector of cellular IFN responses. The importance of IFN signaling in antiviral responses is underscored by the wide variety of strategies that viruses have evolved to evade IFN actions. The viral evasion mechanisms typically involve antagonism of antiviral enzymes that represent important potential targets for therapeutic intervention and rational drug design. ? ? The Paramyxoviridae family of negative-strand RNA viruses includes several well known human pathogens like measles, mumps, respiratory syncytial, and human parainfluenza viruses. Recent findings from the PI's own lab and others indicate that a subset of paramyxoviruses can evade IFN antiviral responses by targeting the STAT protein components of ISGF3 for proteolytic degradation. This STAT protein degradation is mediated by expression of a single viral gene coding for the V protein. Two different paramyxoviruses, simian virus 5 (SV5) and human parainfluenza virus type 2 (HPIV2), evade IFN by targeting the ISGF3 transcription complex, but while the SV5 V protein mediates destruction of STAT1, the HPIV2 V protein mediates destruction of STAT2. The hypothesis that the specificity of V protein-induced STAT recognition and degradation is mediated by discrete protein segments and that V proteins must enlist cellular proteolytic machinery to target specific STAT proteins for proteolysis will be investigated. Chimeric V proteins and STAT proteins will be used in degradation assays to determine the molecular basis for selectivity and specificity in the V protein mediated STAT targeting. V protein-induced modifications of themselves and the STAT targets by ubiquitin and similar ligands will be directly examined in mammalian cells and in vitro ubiquitination assays. GST fusion protein affinity chromatography and immuno-affinity purification strategies will be used to define the cellular machinery involved in this reaction. Together, these experiments will reveal the mechanisms and cellular apparatus used by the paramyxovirus proteins to target and degrade STAT proteins and evade IFN actions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI050707-02
Application #
6640279
Study Section
Experimental Virology Study Section (EVR)
Program Officer
Laughlin, Catherine A
Project Start
2002-07-01
Project End
2007-06-30
Budget Start
2003-07-01
Budget End
2004-06-30
Support Year
2
Fiscal Year
2003
Total Cost
$332,050
Indirect Cost
Name
Mount Sinai School of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
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Rodriguez, Kenny R; Horvath, Curt M (2013) Amino acid requirements for MDA5 and LGP2 recognition by paramyxovirus V proteins: a single arginine distinguishes MDA5 from RIG-I. J Virol 87:2974-8
Bruns, Annie M; Horvath, Curt M (2012) Activation of RIG-I-like receptor signal transduction. Crit Rev Biochem Mol Biol 47:194-206
McErlean, Peter; Greiman, Alyssa; Favoreto Jr, Silvio et al. (2010) Viral diversity in asthma. Immunol Allergy Clin North Am 30:481-95, v

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