Sumoylation coordinates the repression of inflammatory and anti-viral gene-expression programs during innate sensing

Nat Immunol. 2016 Feb;17(2):140-9. doi: 10.1038/ni.3342. Epub 2015 Dec 14.

Abstract

Innate sensing of pathogens initiates inflammatory cytokine responses that need to be tightly controlled. We found here that after engagement of Toll-like receptors (TLRs) in myeloid cells, deficient sumoylation caused increased secretion of transcription factor NF-κB-dependent inflammatory cytokines and a massive type I interferon signature. In mice, diminished sumoylation conferred susceptibility to endotoxin shock and resistance to viral infection. Overproduction of several NF-κB-dependent inflammatory cytokines required expression of the type I interferon receptor, which identified type I interferon as a central sumoylation-controlled hub for inflammation. Mechanistically, the small ubiquitin-like modifier SUMO operated from a distal enhancer of the gene encoding interferon-β (Ifnb1) to silence both basal and stimulus-induced activity of the Ifnb1 promoter. Therefore, sumoylation restrained inflammation by silencing Ifnb1 expression and by strictly suppressing an unanticipated priming by type I interferons of the TLR-induced production of inflammatory cytokines.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Chromatin / genetics
  • Chromatin / metabolism
  • Cytokines / metabolism
  • Dendritic Cells / immunology
  • Dendritic Cells / metabolism
  • Disease Models, Animal
  • Disease Resistance*
  • Disease Susceptibility
  • Enhancer Elements, Genetic
  • Gene Expression Profiling
  • Gene Expression Regulation*
  • Genetic Loci
  • Immunity, Innate*
  • Immunomodulation*
  • Inflammation / genetics*
  • Inflammation / immunology*
  • Inflammation / metabolism*
  • Inflammation / virology
  • Inflammation Mediators / metabolism
  • Interferon-beta / metabolism
  • Lipopolysaccharides / immunology
  • Mice
  • Mice, Knockout
  • Protein Binding
  • Receptor, Interferon alpha-beta / metabolism
  • Regulatory Elements, Transcriptional
  • SUMO-1 Protein / metabolism
  • Shock, Septic / genetics
  • Shock, Septic / immunology
  • Shock, Septic / metabolism
  • Signal Transduction
  • Sumoylation* / genetics
  • Sumoylation* / immunology
  • Toll-Like Receptors / metabolism

Substances

  • Chromatin
  • Cytokines
  • Inflammation Mediators
  • Lipopolysaccharides
  • SUMO-1 Protein
  • Toll-Like Receptors
  • Receptor, Interferon alpha-beta
  • Interferon-beta