Abstract
Severe acute respiratory syndrome (SARS) coronavirus is highly pathogenic in humans and evades innate immunity at multiple levels. It has evolved various strategies to counteract the production and action of type I interferons, which mobilize the front-line defense against viral infection. In this study we demonstrate that SARS coronavirus M protein inhibits gene transcription of type I interferons. M protein potently antagonizes the activation of interferon-stimulated response element-dependent transcription by double-stranded RNA, RIG-I, MDA5, TBK1, IKKϵ, and virus-induced signaling adaptor (VISA) but has no influence on the transcriptional activity of this element when IRF3 or IRF7 is overexpressed. M protein physically associates with RIG-I, TBK1, IKKϵ, and TRAF3 and likely sequesters some of them in membrane-associated cytoplasmic compartments. Consequently, the expression of M protein prevents the formation of TRAF3·TANK·TBK1/IKKϵ complex and thereby inhibits TBK1/IKKϵ-dependent activation of IRF3/IRF7 transcription factors. Taken together, our findings reveal a new mechanism by which SARS coronavirus circumvents the production of type I interferons.
Highlights
The signaling pathways through which viruses induce the production of type I interferons have been well characterized [13,14,15]
These pathways converge on the formation of TRAF31⁄7TANK1⁄7TBK1/IKK⑀ complex, which catalyzes the phosphorylation of IRF3 and IRF7 transcription factors, leading to the activation of type I interferon promoters [15,16,17]
IRF3 phosphorylation was inhibited in cells expressing ORF3b, ORF6, or N protein [7], papain-like protease could physically interact with IRF3 and prevent its phosphorylation and nuclear translocation in a protease-independent manner [11]
Summary
HEK293/ACE2 cells infected with 5 multiplicity of infection of SARS coronavirus or Sendai virus were harvested to 1ϫ SDS gel loading buffer SDS, 10% glycerol, 1% -mercaptoethanol, and 0.02% bromphenol blue) for protein analysis or to cell lysis buffer (50 mM Tris1⁄7Cl, pH 8.0, 140 mM NaCl, 1.5 mM MgCl2, 0.5% Nonidet P-40, and 1 mM dithiothreitol) for RNA analysis. Anti-IFR3, antiTRAF3, anti-IKK⑀, and anti-Myc were from Santa Cruz. Protein Analysis and Reporter Assay—Immunoprecipitation, Western blotting, and dual luciferase assay were carried out as described [41, 42].
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