Viral targeting of the interferon-{beta}-inducing Traf family member-associated NF-{kappa}B activator (TANK)-binding kinase-1.
Expression of the antiviral cytokines IFN-alpha/beta is among the most potent innate defenses of higher vertebrates to virus infections, which is controlled by the inducible transcription factor IFN regulatory factor (IRF)3. Borna disease virus (BDV) establishes persistent noncytolytic infections in animals and tissue culture cells, indicating that it can circumvent this antiviral reaction by an unexplained activity. In this study, we identify the BDV P protein as microbial gene product that associates with and inhibits the principal regulatory kinase of IRF3, Traf family member-associated NF-kappaB activator (TANK)-binding kinase 1 (TBK-1). We demonstrate that the P protein counteracts TBK-1-dependent IFN-beta expression in cells and, hence, the establishment of an antiviral state. Furthermore, our data show that the BDV P protein itself is phosphorylated by TBK-1, suggesting that P functions as a viral decoy substrate that prevents activation of cellular target proteins of TBK-1. Thus, our findings provide evidence for a previously undescribed mechanism by which a viral protein interferes with the induction of the antiviral IFN cascade.
Unterstab
Gunhild
G
Robert Koch Institute, FG12, Nordufer 20, 13353 Berlin, Germany.
Ludwig
Stephan
S
Anton
Aline
A
Planz
Oliver
O
Dauber
Bianca
B
Krappmann
Daniel
D
Heins
Gudrun
G
Ehrhardt
Christina
C
Wolff
Thorsten
T
D000818:Animals; D001890:Borna Disease / Q000378:metabolism*; D001891:Borna disease virus / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism; D004285:Dogs; D006801:Humans; D050838:Interferon Regulatory Factor-3; D016898:Interferon-alpha / Q000096:biosynthesis; D016899:Interferon-beta / Q000096:biosynthesis; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / Q000378:metabolism; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*; D015678:Viral Structural Proteins / Q000235:genetics / Q000378:metabolism*
D004268:DNA-Binding Proteins; C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; D016898:Interferon-alpha; C496537:P protein, Borna disease virus; D010750:Phosphoproteins; D014157:Transcription Factors; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; D014764:Viral Proteins; D015678:Viral Structural Proteins; D016899:Interferon-beta; D017346:Protein Serine-Threonine Kinases; C403191:TBK1 protein, human