The Role Of NDR1 In Antiviral Innate Immune Response

Signal transducers and activators of transcription 1(STAT1)is an important transcriptional factor in type I interferon pathway in antviral innate immunity.However,the regulatory mechanism underlying STAT1 expression remains unclear.Here we report that deficiency or silencing of nuclear Dbf2-related kinase 1(NDR1)in primary macrophages suppresses vesicular stomatitis virus(VSV)and intracellular poly(I:C)induced the production of type I interferon,inflammatory cytokines and interferon stimulated genes(IS Gs).Overexpression of NDR1 or its kinase dead mutants in RAW264.7 significantly enhances VSV induced the production of type I interferon,inflammatory cytokines and antiviral ISGs.Consequently,NDR1 deficency renders the mice more susceptible to VSV infection.Mechanistically,NDR1 has no effect on RIG-? triggered signaling but promotes the translation of STAT1,which is independent of its kinase activity.We further demonstrate that NDR1 upregualtes the expression of NDR1 via inhibiting miRNA146a transcription.NDR1 binds to miRNA146a promoter and interacts with NF-kB to inhibit the transcription of miRNA146a,thereby liberates STAT1 from miRNA146a translational inbibition.Our findings establish NDR1 as a transcriptional regulator of antiviral innate immune responses and indicate a novel mechanism of immunoregulation that involves NDR1-mediated promotion of STAT1 translation.