Noncanonical NF-κB Pathway Controls the Production of Type I Interferons in Antiviral Innate Immunity

• Published in: Immunity (Cambridge, Mass.) Vol. 40; no. 3; pp. 342 - 354
• Main Authors: Jin, Jin, Hu, Hongbo, Li, Haiyan S., Yu, Jiayi, Xiao, Yichuan, Brittain, George C., Zou, Qiang, Cheng, Xuhong, Mallette, Frédérick A., Watowich, Stephanie S., Sun, Shao-Cong
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 20.03.2014
• Subjects: Animals; Cell Differentiation - drug effects; Cell Differentiation - immunology; Dendritic Cells - cytology; Dendritic Cells - immunology; Dendritic Cells - metabolism; Enzyme Activation; Female; Gene Expression Regulation - drug effects; Hematopoietic Cell Growth Factors - pharmacology; Histone Demethylases - metabolism; Histones - metabolism; Immunity, Innate - drug effects; Interferon Type I - biosynthesis; Interferon-beta - genetics; Interferon-beta - metabolism; Ligands; Mice; NF-kappa B - metabolism; NF-kappaB-Inducing Kinase; Promoter Regions, Genetic; Protein Binding; Protein Serine-Threonine Kinases - metabolism; Toll-Like Receptors - metabolism; Transcription Factor RelA - metabolism; Virus Diseases - genetics; Virus Diseases - immunology; Virus Diseases - metabolism
• ISSN: 1074-7613; 1097-4180; 1097-4180
• DOI: 10.1016/j.immuni.2014.02.006

Production of type I interferons (IFN-I) is a crucial innate immune mechanism against viral infections. IFN-I induction is subject to negative regulation by both viral and cellular factors, but the underlying mechanism remains unclear. We report that the noncanonical NF-κB pathway was stimulated along with innate immune cell differentiation and viral infections and had a vital role in negatively regulating IFN-I induction. Genetic deficiencies in major components of the noncanonical NF-κB pathway caused IFN-I hyperinduction and rendered cells and mice substantially more resistant to viral infection. Noncanonical NF-κB suppressed signal-induced histone modifications at the Ifnb promoter, an action that involved attenuated recruitment of the transcription factor RelA and a histone demethylase, JMJD2A. These findings reveal an unexpected function of the noncanonical NF-κB pathway and highlight an important mechanism regulating antiviral innate immunity. •Noncanonical NF-κB is stimulated by viral infection and macrophage differentiation•Noncanonical NF-κB negatively regulates IFN-I induction and antiviral immunity•Noncanonical NF-κB inhibits the recruitment of RelA to Ifnb promoter•Noncanonical NF-κB regulates histone modifications at the Ifnb promoter