C-type lectin DC-SIGN modulates Toll-like receptor signaling via Raf-1 kinase-dependent acetylation of transcription factor NF-kappaB

Immunity. 2007 May;26(5):605-16. doi: 10.1016/j.immuni.2007.03.012. Epub 2007 Apr 26.

Abstract

Adaptive immune responses by dendritic cells (DCs) are critically controlled by Toll-like receptor (TLR) function. Little is known about modulation of TLR-specific signaling by other pathogen receptors. Here, we have identified a molecular signaling pathway induced by the C-type lectin DC-SIGN that modulates TLR signaling at the level of the transcription factor NF-kappaB. We demonstrated that pathogens trigger DC-SIGN on human DCs to activate the serine and threonine kinase Raf-1, which subsequently leads to acetylation of the NF-kappaB subunit p65, but only after TLR-induced activation of NF-kappaB. Acetylation of p65 both prolonged and increased IL10 transcription to enhance anti-inflammatory cytokine responses. We demonstrated that different pathogens such as Mycobacterium tuberculosis, M. leprae, Candida albicans, measles virus, and human immunodeficiency virus-1 interacted with DC-SIGN to activate the Raf-1-acetylation-dependent signaling pathway to modulate signaling by different TLRs. Thus, this pathway is involved in regulation of adaptive immunity by DCs to bacterial, fungal, and viral pathogens.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Amino Acid Motifs
  • Cell Adhesion Molecules / genetics
  • Cell Adhesion Molecules / metabolism*
  • Cells, Cultured
  • DNA / metabolism
  • Enzyme Activation
  • Humans
  • Interleukin-10 / biosynthesis
  • Interleukin-10 / genetics
  • Lectins, C-Type / genetics
  • Lectins, C-Type / metabolism*
  • NF-kappa B / metabolism*
  • Phosphoserine / metabolism
  • Protein Binding
  • Protein-Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins c-raf / metabolism*
  • Receptors, Antigen, T-Cell / metabolism
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / metabolism*
  • Signal Transduction*
  • Toll-Like Receptor 3 / metabolism
  • Toll-Like Receptor 4 / metabolism
  • Toll-Like Receptor 5 / metabolism
  • Toll-Like Receptors / metabolism*
  • Transcription, Genetic / genetics
  • ras Proteins / metabolism

Substances

  • Cell Adhesion Molecules
  • DC-specific ICAM-3 grabbing nonintegrin
  • Lectins, C-Type
  • NF-kappa B
  • Receptors, Antigen, T-Cell
  • Receptors, Cell Surface
  • Toll-Like Receptor 3
  • Toll-Like Receptor 4
  • Toll-Like Receptor 5
  • Toll-Like Receptors
  • Interleukin-10
  • Phosphoserine
  • DNA
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-raf
  • ras Proteins