| Innate imunne system resist pathogens through the recognition of pathogen-associated molecular patterns(PAMPs)by pattern recognition receptors(PRRs).Among various PRRs,Retinoieaeid-indueible gene-I like receptors(RLRs)recognize viral RNA and activate IRF3/7,NF-?B,AP-1 singaling which lead to the production of inflammatory cytokines and type-I interferons(IFNs).Type-I IFNs can trigger the expression of interferon stimulation genes(ISG)through which interfere viral replication after engagement of interferon receptors.Therefore,Type-I IFNs play crucial roles in the innate antiviral immunity.Protein ubiquitination is important to the immune system in spect of singnal transduction and then pathogen clearance.As a member of E3-ubiquitin-ligase,which adding ubiquitins to specific substrates,FBXW7 is reported to modulate multiple biological processes such as tumor growth,lipid metabolism,cell proliferation/differentiation,or the homeostasis of stem cells.However,the role of FBXW7 in innate antiviral immunity is poorly clarified.In our study,we observed that mice with myeloid-specific deficiency of FBXW7(Lysm-Cre+FBXW7f/f)were more susceptible to vesicular stomatitis virus(VSV)infection compared to WT littermates.FBXW7-/-macrophages and dendritic cells(DCs)showed increased levels of VSV-G mRNA after infection both in vitro and in vivo.Further we found that the deficiency of FBXW7 dampened type-I IFNs production by macrophages,moreover,overexpression of FBXW7 enhanced the capacity of macrophages to produce type-I IFNs.After VSV infection,FBXW7 mediated the degradation of phosphatase SHP2,which was a key negative regulator of RIG-I/IRF3 signaling,through interacting with the degron motif of SHP2 and catalyzing K48-linked ubiquitination at K91 locus.Our findings uncover a novel role of FBXW7 in regulating innate antiviral immunity,and may help to provide new strategies for the treatment of viral infection clinically. |
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