Src family kinases Fyn and Lyn are constitutively activated and mediate plasmacytoid dendritic cell responses

Nat Commun. 2017 Apr 3;8:14830. doi: 10.1038/ncomms14830.

Abstract

Plasmacytoid dendritic cells (pDC) are type I interferon-producing cells with critical functions in a number of human illnesses; however, their molecular regulation is incompletely understood. Here we show the role of Src family kinases (SFK) in mouse and human pDCs. pDCs express Fyn and Lyn and their activating residues are phosphorylated both before and after Toll-like receptor (TLR) stimulation. Fyn or Lyn genetic ablation as well as treatment with SFK inhibitors ablate pDC (but not conventional DC) responses both in vitro and in vivo. Inhibition of SFK activity not only alters TLR-ligand localization and inhibits downstream signalling events, but, independent of ex-vivo TLR stimulation, also affects constitutive phosphorylation of BCAP, an adaptor protein bridging PI3K and TLR pathways. Our data identify Fyn and Lyn as important factors that promote pDC responses, describe the mechanisms involved and highlight a tonic SFK-mediated signalling that precedes pathogen encounter, raising the possibility that small molecules targeting SFKs could modulate pDC responses in human diseases.

Publication types

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

MeSH terms

  • Animals
  • Carrier Proteins / metabolism
  • Cytokines / biosynthesis
  • Cytomegalovirus Infections / pathology
  • Cytomegalovirus Infections / virology
  • Dendritic Cells / drug effects
  • Dendritic Cells / enzymology*
  • Endosomes / drug effects
  • Endosomes / metabolism
  • Enzyme Activation / drug effects
  • Humans
  • Ligands
  • Mice, Inbred C57BL
  • Muromegalovirus / physiology
  • Phosphorylation / drug effects
  • Protein Transport / drug effects
  • Proto-Oncogene Proteins c-fyn / metabolism*
  • Pyrimidines / pharmacology
  • Signal Transduction / drug effects
  • TOR Serine-Threonine Kinases / metabolism
  • Toll-Like Receptors / metabolism
  • src-Family Kinases / metabolism*

Substances

  • Carrier Proteins
  • Cytokines
  • Ligands
  • ODF2L protein, human
  • Pyrimidines
  • Toll-Like Receptors
  • Proto-Oncogene Proteins c-fyn
  • lyn protein-tyrosine kinase
  • src-Family Kinases
  • TOR Serine-Threonine Kinases
  • bafetinib