Phase-separated nucleocapsid protein of SARS-CoV-2 suppresses cGAS-DNA recognition by disrupting cGAS-G3BP1 complex

Currently,the incidence and fatality rate of SARS-CoV-2 remain continually high worldwide.COVID-19 patients infected with SARS-CoV-2 exhibited decreased type I interferon(IFN-I)signal,along with limited activation of antiviral immune responses as well as enhanced viral infectivity.Dramatic progresses have been made in revealing the multiple strategies employed by SARS-CoV-2 in impairing canonical RNA sensing pathways.However,it remains to be determined about the SARS-CoV-2 antagonism of cGAS-mediated activation of IFN responses during infection.In the current study,we figure out that SARS-CoV-2 infection leads to the accumulation of released mitochondria DNA(mtDNA),which in turn triggers cGAS to activate IFN-I signaling.As countermeasures,SARS-CoV-2 nucleocapsid(N)protein restricts the DNA recognition capacity of cGAS to impair cGAS-induced IFN-I signaling.Mechanically,N protein disrupts the assembly of cGAS with its co-factor G3BP1 by undergoing DNA-induced liquid-liquid phase separation(LLPS),subsequently impairs the double-strand DNA(dsDNA)detection ability of cGAS.Taken together,our findings unravel a novel antagonistic strategy by which SARS-CoV-2 reduces DNA-triggered IFN-I pathway through interfering with cGAS-DNA phase separation.

Main protease of SARS-CoV-2 serves as a bifunctional molecule in restricting type I interferon antiviral signaling

Dear Editor,At present,the world is suffering from an ongoing pandemic of 2019 novel coronavirus(COVID-19)which is caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2/2019-nCoV).To date,>20 million cases were confirmed with a death toll at>700,000.Although there are no clinically specific and effective antiviral treatments toward SARS-CoV-2 infection so far,the pathological study of SARS-CoV-2 infection and the development of SARS-CoV-2-specific vaccines are progressing rapidly within these several months.1 However,few reports mentioned the mechanism employed by SARS-CoV-2 for evading from surveillance of immune system.

RNA-induced liquid phase separation of SARS-CoV-2 nucleocapsid protein facilitates NF-kB hyper-activation and inflammation

The ongoing 2019 novel coronavirus disease(COVID-19)caused by SARS-CoV-2 has posed a worldwide pandemic and a major global public health threat.The severity and mortality of COVID-19 are associated with virus-induced dysfunctional inflammatory responses and cytokine storms.However,the interplay between host inflammatory responses and SARS-CoV-2 infection remains largely unknown.Here,we demonstrate that SARS-CoV-2 nucleocapsid(N)protein,the major structural protein of the virion,promotes the virus-triggered activation of NF-kB signaling.After binding to viral RNA,N protein robustly undergoes liquid-liquid phase separation(LLPS),which recruits TAK1 and IKK complex,the key kinases of NF-kB signaling,to enhance NF-kB activation.Moreover,1,6-hexanediol,the inhibitor of LLPS,can attenuate the phase separation of N protein and restrict its regulatory functions in NF-kB activation.These results suggest that LLPS of N protein provides a platform to Induce NF-kB hyper-activation,which could be a potential therapeutic target against COVID-19 severe pneumonia.