Vav Proteins Are Key Regulators of Card9 Signaling for Innate Antifungal Immunity

Cell Rep. 2016 Dec 6;17(10):2572-2583. doi: 10.1016/j.celrep.2016.11.018.

Abstract

Fungal infections are major causes of morbidity and mortality, especially in immunocompromised individuals. The innate immune system senses fungal pathogens through Syk-coupled C-type lectin receptors (CLRs), which signal through the conserved immune adaptor Card9. Although Card9 is essential for antifungal defense, the mechanisms that couple CLR-proximal events to Card9 control are not well defined. Here, we identify Vav proteins as key activators of the Card9 pathway. Vav1, Vav2, and Vav3 cooperate downstream of Dectin-1, Dectin-2, and Mincle to engage Card9 for NF-κB control and proinflammatory gene transcription. Although Vav family members show functional redundancy, Vav1/2/3-/- mice phenocopy Card9-/- animals with extreme susceptibility to fungi. In this context, Vav3 is the single most important Vav in mice, and a polymorphism in human VAV3 is associated with susceptibility to candidemia in patients. Our results reveal a molecular mechanism for CLR-mediated Card9 regulation that controls innate immunity to fungal infections.

MeSH terms

  • Animals
  • Antifungal Agents / administration & dosage
  • CARD Signaling Adaptor Proteins / genetics*
  • CARD Signaling Adaptor Proteins / metabolism
  • Candida / genetics
  • Candida / metabolism*
  • Candida / pathogenicity
  • Candidemia / genetics*
  • Candidemia / microbiology
  • Candidemia / pathology
  • Humans
  • Immunity, Innate / genetics*
  • Lectins, C-Type / genetics*
  • Lectins, C-Type / metabolism
  • Membrane Proteins / genetics
  • Mice
  • NF-kappa B / metabolism
  • Proto-Oncogene Proteins c-vav / genetics
  • Signal Transduction / drug effects

Substances

  • Antifungal Agents
  • CARD Signaling Adaptor Proteins
  • Card9 protein, mouse
  • Clecsf8 protein, mouse
  • Lectins, C-Type
  • Membrane Proteins
  • NF-kappa B
  • Proto-Oncogene Proteins c-vav
  • Vav1 protein, mouse
  • Vav2 protein, mouse
  • Vav3 protein, mouse
  • dectin 1
  • dectin-2, mouse