Vav Proteins Are Key Regulators of Card9 Signaling for Innate Antifungal Immunity
Publication year
2016Source
Cell Reports, 17, 10, (2016), pp. 2572-2583ISSN
Publication type
Article / Letter to editor

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Organization
Internal Medicine
Journal title
Cell Reports
Volume
vol. 17
Issue
iss. 10
Page start
p. 2572
Page end
p. 2583
Subject
Radboudumc 4: lnfectious Diseases and Global Health RIMLS: Radboud Institute for Molecular Life SciencesAbstract
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-kappaB 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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- Electronic publications [107155]
- Faculty of Medical Sciences [86157]
- Open Access publications [76288]
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