| Innate immunity is the first line of defense to protect host cells from pathogenic microorganisms infection.It's reported that three PRRs,including NLRs,RLRs and TLRs,could recognize the microbial and viral component.RLRs are important cytoplasmic receptors for the recognition of viral RNA.During viral infection,RIG-I recognizes the virus RNA,which leads to activation after its own conformational change.The activated RIG-I receptor binding VISA and then transduce downstream antiviral innate immune signaling.VISA mediates the activation of NF-?B by activating the IKK?/?/?;on the other hand,it recruits TRAFs through its TRAF-binding motifs to form VISA-TRAFs complex.After that,TBK1 and IKK? are recruiting to promote phosphorylation of IRF3 and IRF7.Phosphorylated IRF3 and IRF7 translocate into the nucleus due to their homologous depolymerization and bind to specific regions of the IFN-? and IFN-? promoter respectively to stimulate the expression of type I interferon.VISA-mediated production of type I interferon plays a crucial role in antiviral innate immunity.However,the mechanisms underlying VISA-mediated antiviral regulation remain unclear.Our research confirme that RACK1 could inhibit RIG-I-,VISA-and TBK1-mediated dimerization of IRF3,SeV-induced activation of IFN-? promoter,interferon-stimulated response element(ISRE)and NF-?B.Knockdown of RACK1 by small interfering RNA could increase RIG/VISA-mediated antiviral transduction.Immunoprecipitation result shows that RACK1 specifically interacts with VISA.Overexpression of RACK1 disrupts formation of the VISA-TRAF2,VISA-TRAF3,and VISA-TRAF6.Futhermore,RACK1 could enhance K48-linked ubiquitination of VISA,attenuate its K63-linked ubiquitination,and decrease VISA-mediated antiviral signal transduction.Together,these results indicate that RACK1 regulates the ubiquitination of VISA to impeding it recruit downstream different TRAF proteins.RACK1 inhibits SeV-induced activation of IRF3 and production of type I interferon. |
PDF Full Text Request