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

TLDR

Paramyxoviruses evade the interferon response by blocking signaling and limiting interferon production, and the IFN‑inducible helicase mda‑5, which contains a caspase recruitment domain, is a key sensor of viral RNA. The conserved cysteine‑rich C‑terminal domain of paramyxovirus V proteins binds mda‑5, and co‑expression of these V proteins suppresses mda‑5–driven activation of the IFN‑β promoter and IFN production, indicating that V proteins inhibit mda‑5 to block interferon induction.

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.