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.

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.

Igniting autophagy through the regulation of phase separation

A recent paper published in Nature by Fujioka et al.demonstrated that the Atg1(also known as ULK1 in mammals)complex undergoes phase separation to form a liquid-like biomolecular condensate,thereby promoting the formation of a preautophagosomal structure(PAS)to activate autophagy in yeast.1 This research discovered the details of a mechanism of phase separation underlying autophagy initiation and provided a better understanding of the biological condensates.