Abstract
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 tran-scription,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 re-sponses of host type Ⅰ interferon.
基金项目
National Natural Science Foundation of China(32170144)
NETL
NSTL
万方数据