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Journal of Virology, February 2009, p. 1465-1473, Vol. 83, No. 3
0022-538X/09/$08.00+0     doi:10.1128/JVI.01768-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Mechanism of mda-5 Inhibition by Paramyxovirus V Proteins{triangledown}

K. S. Childs,1 J. Andrejeva,2 R. E. Randall,2 and S. Goodbourn1*

Division of Basic Medical Sciences, St. George's, University of London, London SW17 0RE, United Kingdom,1 Biomolecular Sciences Building, School of Biology, University of St. Andrews, North Haugh, St. Andrews KY16 9ST, United Kingdom2

Received 21 August 2008/ Accepted 13 November 2008

The RNA helicases encoded by melanoma differentiation-associated gene 5 (mda-5) and retinoic acid-inducible gene I (RIG-I) detect foreign cytoplasmic RNA molecules generated during the course of a virus infection, and their activation leads to induction of type I interferon synthesis. Paramyxoviruses limit the amount of interferon produced by infected cells through the action of their V protein, which binds to and inhibits mda-5. Here we show that activation of both mda-5 and RIG-I by double-stranded RNA (dsRNA) leads to the formation of homo-oligomers through self-association of the helicase domains. We identify a region within the helicase domain of mda-5 that is targeted by all paramyxovirus V proteins and demonstrate that they inhibit activation of mda-5 by blocking dsRNA binding and consequent self-association. In addition to this commonly targeted domain, some paramyxovirus V proteins target additional regions of mda-5. In contrast, V proteins cannot bind to RIG-I and consequently have no effect on the ability of RIG-I to bind dsRNA or to form oligomers.

* Corresponding author. Mailing address: Division of Basic Medical Sciences, St. George's, University of London, London SW17 0RE, United Kingdom. Phone: (44) 20-8725-5942. Fax: (44) 20-8725-2992. E-mail: s.goodbourn{at}sgul.ac.uk

{triangledown} Published ahead of print on 19 November 2008.

Journal of Virology, February 2009, p. 1465-1473, Vol. 83, No. 3
0022-538X/09/$08.00+0     doi:10.1128/JVI.01768-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



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