Sox2 functions as a sequence-specific DNA sensor in neutrophils to initiate innate immunity against microbial infection

Nat Immunol. 2015 Apr;16(4):366-75. doi: 10.1038/ni.3117. Epub 2015 Mar 2.

Abstract

Neutrophils express Toll-like receptors (TLRs) for the recognition of conserved bacterial elements to initiate antimicrobial responses. However, whether other cytosolic DNA sensors are expressed by neutrophils remains elusive. Here we found constitutive expression of the transcription factor Sox2 in the cytoplasm of mouse and human neutrophils. Neutrophil-specific Sox2 deficiency exacerbated bacterial infection. Sox2 directly recognized microbial DNA through its high-mobility-group (HMG) domain. Upon challenge with bacterial DNA, Sox2 dimerization was needed to activate a complex of the kinase TAK1 and its binding partner TAB2, which led to activation of the transcription factors NF-κB and AP-1 in neutrophils. Deficiency in TAK1 or TAB2 impaired Sox2-mediated antibacterial immunity. Overall, we reveal a previously unrecognized role for Sox2 as a cytosolic sequence-specific DNA sensor in neutrophils, which might provide potential therapeutic strategies for the treatment of infectious diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / deficiency
  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / immunology
  • Animals
  • Cytoplasm / immunology
  • Cytoplasm / microbiology
  • DNA, Bacterial / immunology*
  • Gene Expression Regulation
  • Humans
  • Immunity, Innate*
  • Listeria monocytogenes / immunology
  • Listeriosis / genetics
  • Listeriosis / immunology*
  • Listeriosis / microbiology
  • Listeriosis / mortality
  • MAP Kinase Kinase Kinases / deficiency
  • MAP Kinase Kinase Kinases / genetics
  • MAP Kinase Kinase Kinases / immunology
  • Mice
  • NF-kappa B / genetics
  • NF-kappa B / immunology
  • Neutrophils / immunology*
  • Neutrophils / microbiology
  • Protein Multimerization
  • SOXB1 Transcription Factors / genetics
  • SOXB1 Transcription Factors / immunology*
  • Signal Transduction
  • Survival Analysis
  • Toll-Like Receptors / genetics
  • Toll-Like Receptors / immunology
  • Transcription Factor AP-1 / genetics
  • Transcription Factor AP-1 / immunology

Substances

  • Adaptor Proteins, Signal Transducing
  • DNA, Bacterial
  • NF-kappa B
  • SOXB1 Transcription Factors
  • Sox2 protein, mouse
  • Tab2 protein, mouse
  • Toll-Like Receptors
  • Transcription Factor AP-1
  • MAP Kinase Kinase Kinases
  • MAP kinase kinase kinase 7