Akirin2 is critical for inducing inflammatory genes by bridging IκB-ζ and the SWI/SNF complex

EMBO J. 2014 Oct 16;33(20):2332-48. doi: 10.15252/embj.201488447. Epub 2014 Aug 8.

Abstract

Transcription of inflammatory genes in innate immune cells is coordinately regulated by transcription factors, including NF-κB, and chromatin modifiers. However, it remains unclear how microbial sensing initiates chromatin remodeling. Here, we show that Akirin2, an evolutionarily conserved nuclear protein, bridges NF-κB and the chromatin remodeling SWI/SNF complex by interacting with BRG1-Associated Factor 60 (BAF60) proteins as well as IκB-ζ, which forms a complex with the NF-κB p50 subunit. These interactions are essential for Toll-like receptor-, RIG-I-, and Listeria-mediated expression of proinflammatory genes including Il6 and Il12b in macrophages. Consistently, effective clearance of Listeria infection required Akirin2. Furthermore, Akirin2 and IκB-ζ recruitment to the Il6 promoter depend upon the presence of IκB-ζ and Akirin2, respectively, for regulation of chromatin remodeling. BAF60 proteins were also essential for the induction of Il6 in response to LPS stimulation. Collectively, the IκB-ζ-Akirin2-BAF60 complex physically links the NF-κB and SWI/SNF complexes in innate immune cell activation. By recruiting SWI/SNF chromatin remodellers to IκB-ζ, transcriptional coactivator for NF-κB, the conserved nuclear protein Akirin2 stimulates pro-inflammatory gene promoters in mouse macrophages during innate immune responses to viral or bacterial infection.

Keywords: chromatin remodeling; cytokine; gene regulation; innate immunity; macrophages.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Cell Nucleus / metabolism
  • Chromatin Assembly and Disassembly
  • Chromosomal Proteins, Non-Histone / genetics
  • Chromosomal Proteins, Non-Histone / metabolism*
  • Cytokines / metabolism
  • Female
  • Gene Expression Regulation*
  • Humans
  • Immunity, Innate*
  • Listeria monocytogenes / physiology
  • Macrophages / immunology
  • Macrophages / metabolism
  • Male
  • Mice
  • Mice, Knockout
  • Multiprotein Complexes / genetics
  • Multiprotein Complexes / metabolism
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Promoter Regions, Genetic / genetics
  • Protein Binding
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*
  • Sequence Deletion
  • Transcriptional Activation

Substances

  • Adaptor Proteins, Signal Transducing
  • Akirin2 protein, mouse
  • Chromosomal Proteins, Non-Histone
  • Cytokines
  • Multiprotein Complexes
  • Nfkbiz protein, mouse
  • Nuclear Proteins
  • Repressor Proteins