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Published online 9 May 2005 doi:10.1084/jem.20041401
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 201, Number 10, 1543-1553
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ARTICLE

 A cytomegaloviral protein reveals a dual role for STAT2 in IFN-{gamma} signaling and antiviral responses

Albert Zimmermann1, Mirko Trilling2, Markus Wagner3, Manuel Wilborn2, Ivan Bubic4, Stipan Jonjic4, Ulrich Koszinowski3, and Hartmut Hengel1

1 Institut für Virologie, Heinrich-Heine-Universität Düsseldorf, 40225 Düsseldorf, Germany
2 Division of Viral Infections, Robert Koch Institute, 13353 Berlin, Germany
3 Department of Virology, Max von Pettenkofer Institute, 81377 Munich, Germany
4 Department of Histology and Embryology, Faculty of Medicine, University of Rijeka, 51000 Rijeka, Croatia

CORRESPONDENCE Hartmut Hengel: hartmut.hengel{at}uni-duesseldorf.de

A mouse cytomegalovirus (MCMV) gene conferring interferon (IFN) resistance was identified. This gene, M27, encodes a 79-kD protein that selectively binds and down-regulates for signal transducer and activator of transcription (STAT)-2, but it has no effect on STAT1 activation and signaling. The absence of pM27 conferred MCMV susceptibility to type I IFNs ({alpha}/ß), but it had a much more dramatic effect on type II IFNs ({gamma}) in vitro and in vivo. A comparative analysis of M27+ and M27– MCMV revealed that the antiviral efficiency of IFN-{gamma} was partially dependent on the synergistic action of type I IFNs that required STAT2. Moreover, STAT2 was directly activated by IFN-{gamma}. This effect required IFN receptor expression and was independent of type I IFNs. IFN-{gamma} induced increasing levels of tyrosine-phosphorylated STAT2 in M27– MCMV-infected cells that were essential for the antiviral potency of IFN-{gamma}. pM27 represents a new strategy for simultaneous evasions from types I and II IFNs, and it documents an unknown biological significance for STAT2 in antiviral IFN-{gamma} responses.

Abbreviations used: BAC, bacterial artificial chromosome; EMSA, electrophoretic mobility shift assay; GAS, {gamma}-activated sequence; HA, hemagglutinin; HCMV, human CMV; IFNAR, IFN-{alpha}/ß receptor; IFNGR, IFN-{gamma} receptor; IRF, IFN response factor; ISGF3, IFN-stimulated gene factor 3; ISRE, IFN-stimulated response element; MCMV, mouse CMV; MEF, mouse embryonal fibroblast; PAA, phosphonoacetic acid; p.i., postinfection; SG, salivary gland; VV, vaccinia virus.

M. Wagner's present address is Department of Pathology, Harvard Medical School, Boston, MA 02115.


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