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

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

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

Author(s) -

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

Publication year - 2016

Publication title -

cell reports

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 6.264

H-Index - 154

eISSN - 2639-1856

pISSN - 2211-1247

DOI - 10.1016/j.celrep.2016.11.018

Subject(s) - innate immune system , biology , phenocopy , signal transducing adaptor protein , proinflammatory cytokine , transcription factor , acquired immune system , immunology , immunity , context (archaeology) , signal transduction , immune system , syk , microbiology and biotechnology , gene , genetics , phenotype , inflammation , paleontology , tyrosine kinase

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.

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