Innate immunity represents one of the main host responses to viral infection.1,2,3 STING(Stimulator of interferon genes),a crucial immune adapter functioning in host cells,mediates cGAS(Cyclic GMP-AMP Synthase)sensing...Innate immunity represents one of the main host responses to viral infection.1,2,3 STING(Stimulator of interferon genes),a crucial immune adapter functioning in host cells,mediates cGAS(Cyclic GMP-AMP Synthase)sensing of exogenous and endogenous DNA fragments and generates innate immune responses.4 Whether STING activation was involved in infection and replication of enterovirus remains largely unknown.In the present study,we discovered that human enterovirus A71(EV-A71)infection triggered STING activation in a cGAS dependent manner.EV-A71 infection caused mitochondrial damage and the discharge of mitochondrial DNA into the cytosol of infected cells.However,during EV-A71 infection,cGAS-STING activation was attenuated.EV-A71 ^(pro)teins were screened and the viral ^(pro)tease 2A^(pro) had the greatest capacity to inhibit cGAS-STING activation.We identified TRAF3 as an important factor during STING activation and as a target of 2A^(pro).Supplement of TRAF3 rescued cGAS-STING activation suppression by 2A^(pro).TRAF3 supported STING activation mediated TBK1 phosphorylation.Moreover,we found that 2A^(pro) ^(pro)tease activity was essential for inhibiting STING activation.Furthermore,EV-D68 and CV-A16 infection also triggered STING activation.The viral ^(pro)tease 2A^(pro) from EV-D68 and CV-A16 also had the ability to inhibit STING activation.As STING activation prior to EV-A71 infection generated cellular resistance to EV-A71 replication,blocking EV-A71-mediated STING suppression represents a new anti-viral target.展开更多
The emergence of SARS-CoV-2 has resulted in the COVID-19 pandemic,leading to millions of infections and hundreds of thousands of human deaths.The efficient replication and population spread of SARS-CoV-2 indicates an ...The emergence of SARS-CoV-2 has resulted in the COVID-19 pandemic,leading to millions of infections and hundreds of thousands of human deaths.The efficient replication and population spread of SARS-CoV-2 indicates an effective evasion of human innate immune responses,although the viral proteins responsible for this immune evasion are not clear.In this study,we identified SARS-CoV-2 structural proteins,accessory proteins,and the main viral protease as potent inhibitors of host innate immune responses of distinct pathways.In particular,the main viral protease was a potent inhibitor of both the RLR and cGAS-STING pathways.Viral accessory protein 0RF3a had the unique ability to inhibit STING,but not the RLR response.On the other hand,structural protein N was a unique RLR inhibitor.0RF3a bound STING in a unique fashion and blocked the nuclear accumulation of p65 to inhibit nuclear factor-KB signaling.3CL of SARS-CoV-2 inhibited K63-ubiquitin modification of STING to disrupt the assembly of the STING functional complex and downstream signaling.Diverse vertebrate STINGs,including those from humans,mice,and chickens,could be inhibited by 0RF3a and 3CL of SARS-CoV-2.The existence of more effective innate immune suppressors in pathogenic coronaviruses may allow them to replicate more efficiently in vivo.Since evasion of host innate immune responses is essential for the survival of all viruses,our study provides insights into the design of therapeutic agents against SARS-CoV-2.展开更多
基金This work was supported,in part,by following fundings:the National Natural Science Foundation of China(number 31970151,92169203,81701988,31900133,82172239,82102384,32041006,81772169)the National Natural Science Foundation of Zhejiang Province(LQ21C010001 and LY22C080002,)the Leading innovative and Entrepreneur Team Introduction Program of Zhejiang(2019R01007).We thank Yifei Shi kindly provided key reagents.
文摘Innate immunity represents one of the main host responses to viral infection.1,2,3 STING(Stimulator of interferon genes),a crucial immune adapter functioning in host cells,mediates cGAS(Cyclic GMP-AMP Synthase)sensing of exogenous and endogenous DNA fragments and generates innate immune responses.4 Whether STING activation was involved in infection and replication of enterovirus remains largely unknown.In the present study,we discovered that human enterovirus A71(EV-A71)infection triggered STING activation in a cGAS dependent manner.EV-A71 infection caused mitochondrial damage and the discharge of mitochondrial DNA into the cytosol of infected cells.However,during EV-A71 infection,cGAS-STING activation was attenuated.EV-A71 ^(pro)teins were screened and the viral ^(pro)tease 2A^(pro) had the greatest capacity to inhibit cGAS-STING activation.We identified TRAF3 as an important factor during STING activation and as a target of 2A^(pro).Supplement of TRAF3 rescued cGAS-STING activation suppression by 2A^(pro).TRAF3 supported STING activation mediated TBK1 phosphorylation.Moreover,we found that 2A^(pro) ^(pro)tease activity was essential for inhibiting STING activation.Furthermore,EV-D68 and CV-A16 infection also triggered STING activation.The viral ^(pro)tease 2A^(pro) from EV-D68 and CV-A16 also had the ability to inhibit STING activation.As STING activation prior to EV-A71 infection generated cellular resistance to EV-A71 replication,blocking EV-A71-mediated STING suppression represents a new anti-viral target.
基金This work was supported,in part,by funding from the National Natural Science Foundation of China(number 32041006)Zhejiang University special scientific research fund for COVID-19 prevention and control(2020XGZX097)+2 种基金National Natural Science Foundation of Zhejiang Province(LQ21 C010001)the National Natural Science Foundation of China(numbers 31900133,81772169,81802351,81701988,and 31970151)the Chinese Ministry of Science and Technology(number 2018ZX10731-101-001-014).
文摘The emergence of SARS-CoV-2 has resulted in the COVID-19 pandemic,leading to millions of infections and hundreds of thousands of human deaths.The efficient replication and population spread of SARS-CoV-2 indicates an effective evasion of human innate immune responses,although the viral proteins responsible for this immune evasion are not clear.In this study,we identified SARS-CoV-2 structural proteins,accessory proteins,and the main viral protease as potent inhibitors of host innate immune responses of distinct pathways.In particular,the main viral protease was a potent inhibitor of both the RLR and cGAS-STING pathways.Viral accessory protein 0RF3a had the unique ability to inhibit STING,but not the RLR response.On the other hand,structural protein N was a unique RLR inhibitor.0RF3a bound STING in a unique fashion and blocked the nuclear accumulation of p65 to inhibit nuclear factor-KB signaling.3CL of SARS-CoV-2 inhibited K63-ubiquitin modification of STING to disrupt the assembly of the STING functional complex and downstream signaling.Diverse vertebrate STINGs,including those from humans,mice,and chickens,could be inhibited by 0RF3a and 3CL of SARS-CoV-2.The existence of more effective innate immune suppressors in pathogenic coronaviruses may allow them to replicate more efficiently in vivo.Since evasion of host innate immune responses is essential for the survival of all viruses,our study provides insights into the design of therapeutic agents against SARS-CoV-2.