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

2016; Cell Press; Volume: 17; Issue: 10 Linguagem: Inglês

10.1016/j.celrep.2016.11.018

2639-1856

Susanne Roth, Hanna Bergmann, Martin Jaeger, Assa Yeroslaviz, Konstantin Neumann, Paul-Albert Koenig, Clarissa Prazeres da Costa, Lesley Vanes, Vinod Kumar, Melissa D. Johnson, Mauricio Menacho-Márquez, Bianca Habermann, Victor L. J. Tybulewicz, Mihai G. Netea, Xosé R. Bustelo, Jürgen Ruland,

T-cell and B-cell Immunology

Highlights•Vav proteins control CLR-mediated inflammatory responses•CLR-induced NF-κB activation is regulated by Vav proteins•Vav/Card9 signaling is critical for antifungal host defenseSummaryFungal 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.Graphical abstract