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Journal of Virology, February 2009, p. 1299-1311, Vol. 83, No. 3
0022-538X/09/$08.00+0     doi:10.1128/JVI.01659-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

MAVS Dimer Is a Crucial Signaling Component of Innate Immunity and the Target of Hepatitis C Virus NS3/4A Protease{triangledown}

Martin Baril,1 Marie-Eve Racine,1 François Penin,4 and Daniel Lamarre1,2,3*

Institut de Recherche en Immunologie et en Cancérologie (IRIC),1 Département de Médecine, Université de Montréal, Montreal, Québec, Canada H3T 1J4,2 Centre de Recherche du CHUM, Hôpital Saint-Luc, Montreal, Québec, Canada H2X 1P1,3 Institut de Biologie et Chimie des Protéines, UMR 5086 CNRS, Université de Lyon, IFR128 Biosciences Gerland-Lyon Sud, F-69397 Lyon, France4

Received 4 August 2008/ Accepted 17 November 2008

The mitochondrial antiviral signaling (MAVS) protein plays a central role in innate antiviral immunity. Upon recognition of a virus, intracellular receptors of the RIG-I-like helicase family interact with MAVS to trigger a signaling cascade. In this study, we investigate the requirement of the MAVS structure for enabling its signaling by structure-function analyses and resonance energy transfer approaches in live cells. We now report the essential role of the MAVS oligomer in signal transduction and map the transmembrane domain as the main determinant of dimerization. A combination of mutagenesis and computational methods identified a cluster of residues making favorable van der Waals interactions at the MAVS dimer interface. We also correlated the activation of IRF3 and NF-{kappa}B with MAVS oligomerization rather than its mitochondrial localization. Finally, we demonstrated that MAVS oligomerization is disrupted upon expression of HCV NS3/4A protease, suggesting a mechanism for the loss of antiviral signaling. Altogether, our data suggest that the MAVS oligomer is essential in the formation of a multiprotein membrane-associated signaling complex and enables downstream activation of IRF3 and NF-{kappa}B in antiviral innate immunity.

* Corresponding author. Mailing address: Institut de Recherche en Immunologie et en Cancérologie (IRIC), Pavillon Marcelle-Coutu, 2950, chemin Polytechnique, Montréal, Québec, Canada H3T 1J4. Phone: (514) 343-7127. Fax: (514) 343-7780. E-mail: daniel.lamarre{at}umontreal.ca

{triangledown} Published ahead of print on 26 November 2008.

Journal of Virology, February 2009, p. 1299-1311, Vol. 83, No. 3
0022-538X/09/$08.00+0     doi:10.1128/JVI.01659-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



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