NMI Negatively Regulates The Activation Of NF-κB/p65

NF-κB is an important cellular transcription factor.NF-κB regulates diverse genes expression which is involved in many physiological processes such as cell survival and proliferation,apoptosis,cellular stress response,inflammation and immune response.Many stimuli activate NF-κB,and most of these diverse stimuli converge on the IκB kinases(IKK)complexes.Activated IKK phosphorylates IκBa.The phosphorylated IκBα is then ubiquitinated and further degraded by 26S proteasome.The degradation of IKBa releases NF-κB dimer and the free NF-κB dimer enter the nucleus where the NF-κB dimer binds to the promoter or enhancer of the target genes to regulate the expression of these genes.As NF-κB participates in many important physiological processes,the dyregulation of NF-κB causes many diseases.For many years,the NF-κB research is an active field.NMI is an IFN-inducible protein that interacts with a variety of key transcription factors,including C-MYC,N-MYC,Max,IFP35,c-Fos and STAT proteins with the exception of STAT2.NMI can augment IL-2 and IFN-dependent transcription by enhancing the association of p300/CBP coactivator proteins with STAT1 and STAT5.It is reported that NMI is induced by Sendai virus,and it interacts with IFN regulatory factor 7,which promotes the degradation of IFN regulatory factor 7 by uniquitination and inhibits virus-triggered type 1 IFN production.In addition,NMI is a negative regulator of EMT.NMI inhibits the migration of tumor cells.NMI can also retard tumor cell growth by up-regulating DKK1 which is a component of Wnt/β-catenin signaling pathway.All these studies suggest that NMI is an important regulatory protein relevant to inflammation,immune responses and tumorigenesis.NMI binds to many transcriptional factors and modulates their functions.However,whether NMI regulates NF-κB activity is unknown.We found that NMI regulates the activation of NF-κB.HeLa cells produce IL-6 by NF-κB signaling pathway after TNFa stimulation,and NMI negatively regulates TNFa-induced IL-6 production.Overexpression of NMI inhibits NF-κB transcriptional activity,and this suppression is more evident when cells are stimulated with TNFα.Conversely,depletion of NMI by shRNA increased NF-κB transcriptional activity.Mechanistically,NMI,IκcBα and p65 form a complex which doesn’t affect the degradation of IκBα but affect the nuclear transportion of p65.Our findings reveal a new mechanism that controls NF-κB activity.