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 elementdependent transcription by double-stranded RNA, RIG-I, MDA5, TBK1, IKK⑀, 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, IKK⑀, and TRAF3 and likely sequesters some of them in membrane-associated cytoplasmic compartments. Consequently, the expression of M protein prevents the formation of TRAF3⅐TANK⅐TBK1/IKK⑀ complex and thereby inhibits TBK1/IKK⑀-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.
Severe acute respiratory syndrome (SARS)2 coronavirus causes a highly lethal infectious disease in humans characterized by an aberrant immune response (1). The production and action of type I interferons, which are major components of antiviral innate immunity (2, 3), are inhibited at multiple levels by SARS coronavirus (4, 5). This inhibition is thought to be mediated through viral structural and nonstructural proteins N, ORF3b, ORF6, nsp1, and papain-like protease (6 -12).The signaling pathways through which viruses induce the production of type I interferons have been well characterized (13)(14)(15). In response to double-stranded RNA (dsRNA) produced during viral replication, endosomal Toll-like receptor 3 (TLR3) and cytoplasmic retinoic acid-inducible gene I (RIG-I) trigger the activation of two different pathways adapted to downstream kinases through TRIF (TLR adaptor inducing interferon ) and VISA, respectively. These pathways converge on the formation of TRAF3⅐TANK⅐TBK1/IKK⑀ complex, which catalyzes the phosphorylation of IRF3 and IRF7 transcription factors, leading to the activation of type I interferon promoters (15-17).SARS coronaviral proteins counteract the production of type I interferons at multiple steps. Although 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). In addition, nsp1 suppressed the synthesis of host proteins including interferons by inducing mRNA degradation (6, 12). Meanwhile, viral proteins such as nsp1 and ORF6 were multifunctional (10,18,19) and could also inhibit interferon signaling. For example, both nsp1 and ORF6 inhibited the activity of STAT1, a key regulator of interferon-responsive genes (8, 9). Whereas nsp1 attenuated phosphorylati...