The mengovirus leader protein blocks interferon-alpha/beta gene transcription and inhibits activation of interferon regulatory factor 3.
Viral infection of mammalian cells triggers the synthesis and secretion of type I interferons (i.e. IFN-alpha/beta), which induce the transcription of genes that cause cells to adopt an antiviral state. Many viruses have adapted mechanisms to evade IFN-alpha/beta-mediated responses. The leader protein of mengovirus, a picornavirus, has been implicated as an IFN-alpha/beta antagonist. Here, we show that the leader inhibits the transcription of IFN-alpha/beta and that both the presence of a zinc finger motif in its N-terminus and phosphorylation of threonine-47 are required for this function. Transcription of IFN-alpha/beta genes relies on the activity of a number of transcription factors, including interferon regulatory factor 3 (IRF-3). We show that the leader interferes with the transactivation activity of IRF-3 by interfering with its dimerization. Accordingly, mutant viruses with a disturbed leader function were impaired in their ability to suppress IFN-alpha/beta transcription in vivo. By consequence, the leader mutant viruses had an impaired ability to replicate and spread in normal mice but not in IFNAR-KO mice, which are incapable of mounting an IFN-alpha/beta-dependent antiviral response. These results suggest that the leader, by suppressing IRF3-mediated IFN-alpha/beta production, plays an important role in replication and dissemination of mengovirus in its host.
Hato
Stanleyson V
SV
Department of Medical Microbiology, Radboud University Nijmegen Medical Centre, Nijmegen Centre for Molecular Life Sciences, Nijmegen, The Netherlands.
Ricour
Celine
C
Schulte
Barbara M
BM
Lanke
Kjerstin H W
KH
de Bruijni
Mike
M
Zoll
Jan
J
Melchers
Willem J G
WJ
Michiels
Thomas
T
van Kuppeveld
Frank J M
FJ
D000818:Animals; D018188:Cardiovirus Infections / Q000276:immunology; D019281:Dimerization; D015536:Down-Regulation; D005260:Female; D050838:Interferon Regulatory Factor-3 / Q000037:antagonists & inhibitors*; D016898:Interferon-alpha / Q000096:biosynthesis*; D016899:Interferon-beta / Q000096:biosynthesis*; D008574:Mengovirus / Q000235:genetics / Q000254:growth & development / Q000276:immunology*; D051379:Mice; D016019:Survival Analysis; D014764:Viral Proteins / Q000235:genetics / Q000502:physiology*; D014774:Virulence; D014779:Virus Replication / Q000276:immunology
D050838:Interferon Regulatory Factor-3; D016898:Interferon-alpha; D014764:Viral Proteins; D016899:Interferon-beta