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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Roth, S; Bergmann, H; Jaeger, M; Yeroslaviz, A; Neumann, K; Koenig, P-A; Prazeres da Costa, C; Vanes, L; Kumar, V; Johnson, M; Menacho-Márquez, M; Habermann, B; Tybulewicz, VL; Netea, M; Bustelo, XR; Ruland, J

Published Date

  • December 6, 2016

Published In

Volume / Issue

  • 17 / 10

Start / End Page

  • 2572 - 2583

PubMed ID

  • 27926862

Pubmed Central ID

  • PMC5177621

Electronic International Standard Serial Number (EISSN)

  • 2211-1247

Digital Object Identifier (DOI)

  • 10.1016/j.celrep.2016.11.018


  • eng

Conference Location

  • United States