Molecular Mechanisms Of The Inhibition Of Interferon-beta Induction By The Nucleocapsid Protein Of Severe Acute Respiratory Syndrome Coronavirus

Severe acute respiratory syndrome (SARS) is a highly contagious and lethal disease caused by a new type of coronavirus, SARS-associated coronavirus (SARS-CoV). Currently, there is no efficient treatment and prevention for this disease. Production of interferon (IFN) is one of the primary host defense mechanism. However, SARS-CoV infection does not result in IFN production.As in other coronaviruses, nucleocapsid (N) is one of the most crucial structural components of the SARS-CoV. Besides being the capsid protein of the virus, N protein is known to inhibit the synthesis of interferon. In this study, we explore the molecular mechanism how the N protein interferes with the innate immunity.We found that the N protein of SARS-CoV could inhibit interferon-beta (IFNβ) production activated by Sendai Virus or polyI:C but not by the downstream adaptors of two major signaling pathways which lead to activation of type I interferon responses following virus infection. We observed that N protein inhibited the nuclear translocation of IRF3 promoted by polyI:C,3'UTR of HCV and short dsRNA while it could not inhibit the nuclear translocation of IRF3 promoted by overexpression of VISA, TBK1, TRIF or IKKε. N could inhibit the dimer formation of IRF3 promoted by polyI:C, but it could only partly influence the dimer formation of IRF3 promoted by overexpression of VISA, TBK1, TRIF or IKKε.Furthermore, we found that N protein could reduce the RIG-I binding to RNAs in vitro. Therefore, we propose that SARS N protein may function by shielding of the RNAs which elicit an interferon response from recognition of cellular receptors. In a word, we found a new possibility of nucleocapsid protein in interfering with the innate immunity system. These results provided new insights into understanding the mechanism involved in the function of SARS-CoV N protein and pathogenesis of the virus.