title: Let-7 miRNAs Modulate the Activation of NF-κB by Targeting TNFAIP3 and Are Involved in the Pathogenesis of Lupus Nephritis.
abstract: TNFAIP3 is a ubiquitin-editing enzyme that negatively regulates multiple NF-κB signaling pathways and dysregulation of TNFAIP3 is related to systemic lupus erythematosus (SLE). Although there exists evidence indicating that microRNAs (miRNAs) modulate the expression of TNFAIP3, whether and how miRNAs regulate TNFAIP3 and contribute to lupus nephritis (LN) is still not well understood. In this study, we screened eleven selected miRNAs that potentially regulated TNFAIP3 expression by dual luciferase assay and found that Let-7 miRNAs repressed TNFAIP3 expression by targeting the 3'UTR of TNFAIP3 mRNA. Overexpression of Let-7 miRNAs led to increased phosphorylation and sustained degradation of IκBα and enhanced phosphorylation of p65 following TNFα stimulation and promoted SeV-induced production of cytokines in HEK293T cells. In addition, the expression of Let-7 miRNAs was significantly up-regulated, and TNFAIP3 level was remarkably down-regulated in samples from LN patients compared control samples. Our findings have uncovered Let-7-TNFAIP3-NF-κB pathway that is involved in LN and thus provided a potential target for therapeutic intervention.
authors.affiliation: Department of Nephrology, Shanghai General Hospital, Shanghai Jiaotong University, Shanghai, P.R. China.
authors.forename: Jun
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Nephrology, Shanghai General Hospital, Shanghai Jiaotong University, Shanghai, P.R. China.
authors.forename: Lin
authors.initials: L
authors.lastname: Zhu
authors.affiliation: Department of Nephrology, Shanghai General Hospital, Shanghai Jiaotong University, Shanghai, P.R. China.
authors.forename: Guang-liang
authors.initials: GL
authors.lastname: Xie
authors.affiliation: Department of Nephrology, Shanghai General Hospital, Shanghai Jiaotong University, Shanghai, P.R. China.
authors.forename: Jing-fang
authors.initials: JF
authors.lastname: Bao
authors.affiliation: Department of Nephrology, Shanghai General Hospital, Shanghai Jiaotong University, Shanghai, P.R. China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Yu
mesh_terms: D020413:3' Untranslated Regions; D000328:Adult; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D008181:Lupus Nephritis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D005810:Multigene Family; D016328:NF-kappa B / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation; D015398:Signal Transduction; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3
chemical_list: D020413:3' Untranslated Regions; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D035683:MicroRNAs; D016328:NF-kappa B; D009687:Nuclear Proteins; C487931:mirnlet7 microRNA, human; C076529:TNFAIP3 protein, human; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3