Enterovirus D68(EV-D68)can cause respiratory diseases and acute flaccid paralysis,posing a great threat to public health.Interferons are cytokines secreted by host cells that have broad-spectrum antiviral effects,indu...Enterovirus D68(EV-D68)can cause respiratory diseases and acute flaccid paralysis,posing a great threat to public health.Interferons are cytokines secreted by host cells that have broad-spectrum antiviral effects,inducing the expression of hundreds of interferon-stimulated genes(ISGs).EV-D68 activates ISG expression early in infection,but at a later stage,the virus suppresses ISG expression,a strategy evolved by EV-D68 to antagonize interferons.Here,we explore a host protein,suppressor of cytokine signaling 3(SOCS3),is upregulated during EV-D68 infection and antagonizes the antiviral effects of type I interferon.We subsequently demonstrate that the structural protein of EV-D68 upregulated the expression of RFX7,a transcriptional regulator of SOCS3,leading to the upregulation of SOCS3 expression.Further exploration revealed that SOCS3 plays its role by inhibiting the phosphorylation of signal transducer and activator of transcription 3(STAT3).The expression of SOCS3 inhibited the expression of ISG,thereby inhibiting the antiviral effect of type I interferon and promoting EV-D68 transcription,protein production,and viral titer.Notably,a truncated SOCS3,generated by deleting the kinase inhibitory region(KIR)domain,failed to promote replication and translation of EV-D68.Based on the above studies,we designed a short peptide named SOCS3 inhibitor,which can specifically bind and inhibit the KIR structural domain of SOCS3,significantly reducing the RNA and protein levels of EV-D68.In summary,our results demonstrated a novel mechanism by which EV-D68 inhibits ISG transcription and antagonizes the antiviral responses of host type I interferon.展开更多
Phenuiviridae,a member of the Bunyavirales order,can lead to significant human morbidity and mortality.Various phenuiviruses target specific cellular proteins and have strategies to counteract the effects of type I in...Phenuiviridae,a member of the Bunyavirales order,can lead to significant human morbidity and mortality.Various phenuiviruses target specific cellular proteins and have strategies to counteract the effects of type I interferon(IFN).Previous studies have shown that phenuiviruses infection inhibits the synthesis of type I IFNs,and viral nonstructural proteins(NSs)had been further identified as an IFN antagonist.This study found that the NSs proteins of Dabie bandavirus(DBV),Sandfly fever Sicilian virus(SFSV),and Uukuniemi virus(UUKV)can inhibit Sendai virus-induced activation of IFN-βpromoter and phosphorylation of IFN regulatory factor 3(IRF3).Moreover,detailed analysis revealed that the phenuivirus NSs protein could directly interact with retinoic acid inducible gene-I(RIG-I)and degrade it via a proteasome-dependent pathway.In short,this study demonstrate a novel mechanism of phenuiviruses to resist host antiviral immunity,which may help understand these pathogens and suggest novel therapeutic approaches.展开更多
基金This work was supported by the National Natural Science Foundation of China(32170144).
文摘Enterovirus D68(EV-D68)can cause respiratory diseases and acute flaccid paralysis,posing a great threat to public health.Interferons are cytokines secreted by host cells that have broad-spectrum antiviral effects,inducing the expression of hundreds of interferon-stimulated genes(ISGs).EV-D68 activates ISG expression early in infection,but at a later stage,the virus suppresses ISG expression,a strategy evolved by EV-D68 to antagonize interferons.Here,we explore a host protein,suppressor of cytokine signaling 3(SOCS3),is upregulated during EV-D68 infection and antagonizes the antiviral effects of type I interferon.We subsequently demonstrate that the structural protein of EV-D68 upregulated the expression of RFX7,a transcriptional regulator of SOCS3,leading to the upregulation of SOCS3 expression.Further exploration revealed that SOCS3 plays its role by inhibiting the phosphorylation of signal transducer and activator of transcription 3(STAT3).The expression of SOCS3 inhibited the expression of ISG,thereby inhibiting the antiviral effect of type I interferon and promoting EV-D68 transcription,protein production,and viral titer.Notably,a truncated SOCS3,generated by deleting the kinase inhibitory region(KIR)domain,failed to promote replication and translation of EV-D68.Based on the above studies,we designed a short peptide named SOCS3 inhibitor,which can specifically bind and inhibit the KIR structural domain of SOCS3,significantly reducing the RNA and protein levels of EV-D68.In summary,our results demonstrated a novel mechanism by which EV-D68 inhibits ISG transcription and antagonizes the antiviral responses of host type I interferon.
基金We thank Liu Yang for assistance in the confocal microscopy studies.We also thank Lishu Zheng for providing Sendai virus.This work was supported by the National Science Foundation of China(grant numbers 31270201)the National Basic Research Program(973 Program)of China(grant numbers 2011CB504700).
文摘Phenuiviridae,a member of the Bunyavirales order,can lead to significant human morbidity and mortality.Various phenuiviruses target specific cellular proteins and have strategies to counteract the effects of type I interferon(IFN).Previous studies have shown that phenuiviruses infection inhibits the synthesis of type I IFNs,and viral nonstructural proteins(NSs)had been further identified as an IFN antagonist.This study found that the NSs proteins of Dabie bandavirus(DBV),Sandfly fever Sicilian virus(SFSV),and Uukuniemi virus(UUKV)can inhibit Sendai virus-induced activation of IFN-βpromoter and phosphorylation of IFN regulatory factor 3(IRF3).Moreover,detailed analysis revealed that the phenuivirus NSs protein could directly interact with retinoic acid inducible gene-I(RIG-I)and degrade it via a proteasome-dependent pathway.In short,this study demonstrate a novel mechanism of phenuiviruses to resist host antiviral immunity,which may help understand these pathogens and suggest novel therapeutic approaches.
