Vav proteins are key regulators of Card9 signaling for innate antifungal immunityMore about Open Access at the Crick
Authors listSusanne Roth Hanna Bergmann Martin Jaeger Assa Yeroslaviz Konstantin Neumann Paul-Albert Koenig Clarissa Prazeres da Costa Lesley Vanes Vinod Kumar Melissa Johnson Mauricio Menacho-Márquez Bianca Habermann Victor Tybulewicz Mihai Netea Xosé R Bustelo Jürgen Ruland
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.
Journal Cell Reports
Issue number 10