Noncanonical NF-κB pathway controls the production of type I interferons in antiviral innate immunity

Immunity. 2014 Mar 20;40(3):342-54. 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • 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*
  • 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*


  • Hematopoietic Cell Growth Factors
  • Histones
  • Interferon Type I
  • Ligands
  • NF-kappa B
  • Toll-Like Receptors
  • Transcription Factor RelA
  • Interferon-beta
  • Histone Demethylases
  • JMJD2A protein, mouse
  • Protein Serine-Threonine Kinases
  • NF-kappa B kinase