A cytomegaloviral protein reveals a dual role for STAT2 in IFN-{gamma} signaling and antiviral responses.
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/beta), 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.
Zimmermann
Albert
A
Institut für Virologie, Heinrich-Heine-Universität Düsseldorf, 40225 Düsseldorf, Germany.
Trilling
Mirko
M
Wagner
Markus
M
Wilborn
Manuel
M
Bubic
Ivan
I
Jonjic
Stipan
S
Koszinowski
Ulrich
U
Hengel
Hartmut
H
D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000276:immunology*; D005786:Gene Expression Regulation / Q000276:immunology; D006566:Herpesviridae Infections / Q000235:genetics / Q000276:immunology*; D007372:Interferons / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D018146:Muromegalovirus / Q000235:genetics / Q000276:immunology*; D017471:Receptors, Interferon / Q000096:biosynthesis; D050795:STAT2 Transcription Factor; D015398:Signal Transduction / Q000276:immunology*; D015534:Trans-Activators / Q000276:immunology*; D014158:Transcription, Genetic / Q000276:immunology; D015533:Transcriptional Activation / Q000276:immunology; D014764:Viral Proteins / Q000235:genetics / Q000276:immunology*
D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D017471:Receptors, Interferon; D050795:STAT2 Transcription Factor; C494085:Stat2 protein, mouse; D015534:Trans-Activators; D014764:Viral Proteins; D007372:Interferons