At present, the novel severe acute respiratory syndrome (SARS) coronavirus 2 (SARS-CoV-2) is widely spreading around the world, and there is no specific medicine controlling SARS-CoV-2. In July 8th, 2021, professor Zhou Fangfang's research group in institutes of biology and medical science (IBMS), Soochow University published their novel research results entitled “Targeting liquid-liquid phase separation of SARS-CoV-2 nucleocapsid protein promotes innate antiviral immunity via elevating MAVS activity” in Nature Cell Biology.
Elucidating the immune escape mechanism of SARS-CoV-2 may guide the development of specific treatment of COVID-19. The type I interferon mediated innate antiviral response is vital for host’s defense against invading pathogens. Nevertheless, patients with COVID-19 exhibit dysregulated IFN-I production and compromised antiviral response. This study identified the SARS-CoV-2 nucleocapsid protein (NP) as an inhibitor of innate antiviral immune signaling via restricting the activation of MAVS, a critical adaptor protein in innate immunity. Moreover, NP was found to undergo liquid-liquid phase separation (LLPS) dependent of its C-terminal dimerization domain. Interestingly, NP LLPS was indispensable for its immunosuppression. Lack of dimerization domain or acetylation at Lys375 could not only abolish NP LLPS, but also dampen its immunosuppressive activity. The acetyltransferase CBP mediates the acetylation of NP k375 site, which may be a host defense mechanism. A variety of interfering peptide targeting NP dimerization domain were designed and NIP-V was screened out to disrupt NP phase separation and rescue innate antiviral immunity. Upon SARS-CoV-2 infection, NIP-V-treated human ACE2 transgenic mice displayed enhanced innate antiviral response, low viral loads and reduced lung lesions. Collectively, this study revealed the molecular mechanism by which SARS-CoV-2 NP inhibits host antiviral innate immunity dependent of its phase separation, and further explored the possibility of interfering with NP phase separation to rescue host antiviral immunity and inhibit the proliferation of SARS-CoV-2, paving the way for development of specific drugs for COVID-19. Nature Cell Biology published a special article to comment on the academic significance of the research: “SARS-CoV-2 targets MAVS for immune evasion”.
Wang Shuai, Dai tong, Qin Ziran and Pan Ting are the first authors of this paper. Professor Zhou Fangfang is the corresponding author of the paper. This work is supported by a special program from the Ministry of Science and Technology of China (2016YFA0502500), the Chinese National Natural Science Funds (U20A201376, 82041009, 31871405, 91753139, 31925013, 31671457, 31571460, 31870902, 32070907, 31871405,31771619, 92053114和32070632), National Postdoctoral Program for Innovative Talent (BX2021208), Jiangsu National Science Foundation (BK20180043 and 19KJA550003).
Paper：https://www.nature.com/articles/s41556-021-00710-0
Comment：https://www.nature.com/articles/s41556-021-00712-y#auth-Luke_A__J_-O_Neil