The V proteins of paramyxoviruses bind the IFN-inducible RNA helicase, mda-5, and inhibit its activation of the IFN-β promoter

doi:10.1073/pnas.0407639101

The V proteins of paramyxoviruses bind the IFN-inducible RNA helicase, mda-5, and inhibit its activation of the IFN-β promoter

^*School of Biology, Biomolecular Sciences Building, North Haugh, University of St. Andrews, Fife KY16 9TS, United Kingdom; and ^†Biochemistry and Immunology, Department of Basic Medical Sciences, St. George's Hospital Medical School, University of London, London SW17 0RE, United Kingdom

Communicated by Robert A. Lamb, Northwestern University, Evanston, IL, October 15, 2004 (received for review September 28, 2004)

Abstract

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-β promoter in reporter gene assays and significantly enhanced the activation of the IFN-β 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-β 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-β promoter, and that the V proteins of paramyxoviruses interact with mda-5 to block its activity.

Footnotes

↵ ‡ To whom correspondence should be addressed. E-mail: rer{at}st-and.ac.uk.
Author contributions: J.A., S.G., K.S.C., and R.E.R. designed research; J.A., K.S.C., D.F.Y., T.S.C., N.S., and S.G. performed research; S.G. and R.E.R. analyzed data; and R.E.R. and S.G. wrote the paper.
Abbreviations: PIV, parainfluenza viruses; SeV, Sendai virus; SV5, simian virus 5; HeV, Hendra virus; mda-5, melanoma differentiation-associated gene 5; CARD, caspase recruitment domain; RNAi, RNA interference; RIG-I, retinoic acid inducible gene I; IRF, IFN regulatory factor.