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

ROTH, SUSANNE; BERGMANN, HANNA; JAEGER, MARTIN; YEROSLAVIZ, ASSA; NEUMANN, KONSTANTIN; KOENIG, PAUL-ALBERT; PRAZERES DA COSTA, CLARISSA; VANES, LESLEY; KUMAR, VINOD; JOHNSON, MELISSA; MENACHO-MÁRQUEZ, MAURICIO; HABERMANN, BIANCA; TYBULEWICZ, VICTOR L.; NETEA, MIHAI; BUSTELO, XOSÉ R.; RULAND, JÜRGEN

Cell Reports

Elsevier B.V.

Año: 2016 vol. 17 p. 2572 - 2583

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.