Thogoto virus ML protein suppresses IRF3 function.
The Thogoto virus (THOV) is a member of the family Orthomyxoviridae. It prevents induction of alpha/beta interferons (IFN) in cell culture and in vivo via the action of the viral ML protein. Phenotypically, the effect of THOV ML resembles that of the NS1 protein of influenza A virus (FLUAV) in that it blocks the expression of IFN genes. IFN expression depends on IFN regulatory factor 3 (IRF3). Upon activation, IRF3 forms homodimers and accumulates in the nucleus where it binds the transcriptional coactivator CREB-binding protein (CBP). Here, we show that expression of ML blocked the transcriptional activity of IRF3 after stimulation by virus infection. Further biochemical analysis revealed that ML acts by blocking IRF3 dimerization and association with CBP. Surprisingly, however, ML did not interfere with the nuclear transport of IRF3. Thus, the action of ML differs strikingly from that of FLUAV NS1 that prevents IFN induction by retaining IRF3 in the cytoplasm.
Jennings
Stephanie
S
Abteilung Virologie, Institut für Medizinische Mikrobiologie und Hygiene, Universität Freiburg, D-79008 Freiburg, Germany.
Martínez-Sobrido
Luis
L
García-Sastre
Adolfo
A
Weber
Friedemann
F
Kochs
Georg
G
D000818:Animals; D050882:CREB-Binding Protein; D002467:Cell Nucleus / Q000378:metabolism; D002522:Chlorocebus aethiops; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology; D015967:Gene Expression Regulation, Viral / Q000502:physiology*; D006801:Humans; D050838:Interferon Regulatory Factor-3; D009687:Nuclear Proteins / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000502:physiology; D011485:Protein Binding; D018117:Thogotovirus / Q000235:genetics / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology; D014709:Vero Cells; D014764:Viral Proteins / Q000502:physiology*
D004268:DNA-Binding Proteins; C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; D009687:Nuclear Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D014764:Viral Proteins; D050882:CREB-Binding Protein; C494363:CREBBP protein, human