The V proteins of paramyxoviruses bind the IFN-inducible RNA helicase, mda-5, and inhibit its activation of the IFN-beta promoter.
Most paramyxoviruses circumvent the IFN response by blocking IFN signaling and limiting the production of IFN by virus-infected cells. Here we report that the highly conserved cysteine-rich C-terminal domain of the V proteins of a wide variety of paramyxoviruses binds melanoma differentiation-associated gene 5 (mda-5) product. mda-5 is an IFN-inducible host cell DExD/H box helicase that contains a caspase recruitment domain at its N terminus. Overexpression of mda-5 stimulated the basal activity of the IFN-beta promoter in reporter gene assays and significantly enhanced the activation of the IFN-beta promoter by intracellular dsRNA. Both these activities were repressed by coexpression of the V proteins of simian virus 5, human parainfluenza virus 2, mumps virus, Sendai virus, and Hendra virus. Similar results to the reporter assays were obtained by measuring IFN production. Inhibition of mda-5 by RNA interference or by dominant interfering forms of mda-5 significantly inhibited the activation of the IFN-beta promoter by dsRNA. It thus appears that mda-5 plays a central role in an intracellular signal transduction pathway that can lead to the activation of the IFN-beta promoter, and that the V proteins of paramyxoviruses interact with mda-5 to block its activity.
Andrejeva
J
J
School of Biology, Biomolecular Sciences Building, North Haugh, University of St. Andrews, Fife KY16 9TS, United Kingdom.
Childs
K S
KS
Young
D F
DF
Carlos
T S
TS
Stock
N
N
Goodbourn
S
S
Randall
R E
RE
D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D053487:DEAD-box RNA Helicases; D006801:Humans; D000072640:Interferon-Induced Helicase, IFIH1; D016899:Interferon-beta / Q000235:genetics*; D010252:Paramyxoviridae / Q000737:chemistry*; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011485:Protein Binding; D020365:RNA Helicases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D015398:Signal Transduction; D015533:Transcriptional Activation / Q000187:drug effects*; D014162:Transfection; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology
D034741:RNA, Small Interfering; D014764:Viral Proteins; D016899:Interferon-beta; C452815:IFIH1 protein, human; D053487:DEAD-box RNA Helicases; D000072640:Interferon-Induced Helicase, IFIH1; D020365:RNA Helicases