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Journal of Virology, September 2008, p. 8330-8338, Vol. 82, No. 17
0022-538X/08/$08.00+0     doi:10.1128/JVI.00831-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

STAT2 Is a Primary Target for Measles Virus V Protein-Mediated Alpha/Beta Interferon Signaling Inhibition{triangledown}

Aparna Ramachandran,1,2 Jean-Patrick Parisien,1,2,3 and Curt M. Horvath1,2,3*

Department of Medicine,1 Department of Biochemistry, Molecular Biology, and Cell Biology, Northwestern University,2 Department of Medicine, Evanston Northwestern Healthcare, Evanston, Illinois 602083

Received 17 April 2008/ Accepted 17 June 2008

Measles virus, a member of the Morbillivirus family, infects millions of people each year despite the availability of effective vaccines. The V protein of measles virus is an important virulence factor that can interfere with host innate immunity by inactivating alpha/beta interferon (IFN-{alpha}/β) and IFN-{gamma} signaling through protein interactions with signal transducer and activator of transcription proteins STAT1 and STAT2. Here we demonstrate that although STAT1 interference results from protein interactions within a V protein N-terminal region encompassed by amino acids 110 to 130, detection of STAT1 interaction and IFN-{gamma} signaling inhibition requires the presence of cellular STAT2. Cell-specific variability in STAT1 interference was observed to correlate with V protein expression level. A more direct target for measles virus V protein-mediated IFN-{alpha}/β evasion is STAT2. Results indicate that the widely conserved C-terminal zinc finger domain of measles virus V protein is both necessary and sufficient to bind STAT2 and disrupt IFN-{alpha}/β signal transduction. Mutagenesis and molecular modeling define a contact surface for STAT2 association that includes aspartic acid residue 248 as critical for STAT2 interference and IFN antiviral immune suppression. These findings clearly define the molecular determinants for measles virus IFN evasion and validate specific targets as candidates for therapeutic intervention.

* Corresponding author. Mailing address: Pancoe ENH Pavilion, Rm. 4401, 2200 Campus Drive, Evanston, IL 60208. Phone: (847) 491-5530. Fax: (847) 491-4400. E-mail: horvath{at}northwestern.edu

{triangledown} Published ahead of print on 25 June 2008.

Journal of Virology, September 2008, p. 8330-8338, Vol. 82, No. 17
0022-538X/08/$08.00+0     doi:10.1128/JVI.00831-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Parisien, J.-P., Bamming, D., Komuro, A., Ramachandran, A., Rodriguez, J. J., Barber, G., Wojahn, R. D., Horvath, C. M. (2009). A Shared Interface Mediates Paramyxovirus Interference with Antiviral RNA Helicases MDA5 and LGP2. J. Virol. 83: 7252-7260 [Abstract] [Full Text]  
  • Toth, A. M., Devaux, P., Cattaneo, R., Samuel, C. E. (2009). Protein Kinase PKR Mediates the Apoptosis Induction and Growth Restriction Phenotypes of C Protein-Deficient Measles Virus. J. Virol. 83: 961-968 [Abstract] [Full Text]  


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