Hepatitis A virus suppresses RIG-I-mediated IRF-3 activation to block induction of beta interferon.
Hepatitis A virus (HAV) antagonizes the innate immune response by inhibition of double-stranded RNA (dsRNA)-induced beta interferon (IFN-beta) gene expression. In this report, we show that this is due to an interaction of HAV with the intracellular dsRNA-induced retinoic acid-inducible gene I (RIG-I)-mediated signaling pathway upstream of the kinases responsible for interferon regulatory factor 3 (IRF-3) phosphorylation (TBK1 and IKKepsilon). In consequence, IRF-3 is not activated for nuclear translocation and gene induction. In addition, we found that HAV reduces TRIF (TIR domain-containing adaptor inducing IFN-beta)-mediated IRF-3 activation, which is part of the Toll-like receptor 3 signaling pathway. As IRF-3 is necessary for IFN-beta transcription, inhibition of this factor results in efficient suppression of IFN-beta synthesis. This ability of HAV seems to be of considerable importance for HAV replication, as HAV is not resistant to IFN-beta, and it may allow the virus to establish infection and preserve the sites of virus production in later stages of the infection.
Fensterl
Volker
V
Department of Virology, University of Bremen, Germany.
Grotheer
Dajana
D
Berk
Iris
I
Schlemminger
Stefanie
S
Vallbracht
Angelika
A
Dotzauer
Andreas
A
D000818:Animals; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006506:Hepatitis A / Q000276:immunology* / Q000378:metabolism; D030041:Hepatitis A virus / Q000254:growth & development / Q000472:pathogenicity*; D006801:Humans; D051550:I-kappa B Kinase; D050838:Interferon Regulatory Factor-3; D016899:Interferon-beta / Q000037:antagonists & inhibitors* / Q000235:genetics; D008562:Membrane Glycoproteins / Q000737:chemistry / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D017434:Protein Structure, Tertiary; D020365:RNA Helicases / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000378:metabolism; D011971:Receptors, Immunologic; D015398:Signal Transduction; D051196:Toll-Like Receptor 3; D051193:Toll-Like Receptors; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic
D004268:DNA-Binding Proteins; C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3; D051193:Toll-Like Receptors; D014157:Transcription Factors; D016899:Interferon-beta; D017346:Protein Serine-Threonine Kinases; C403191:TBK1 protein, human; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human; C452820:RIGI protein, human; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases; D020365:RNA Helicases