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Vav proteins are key regulators of Card9 signaling for innate antifungal immunity

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 an...

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Main Authors: Roth, Susanne (Author) , Bergmann, Hanna (Author) , Jaeger, Martin (Author) , Yeroslaviz, Assa (Author) , Neumann, Konstantin (Author) , Koenig, Paul-Albert (Author) , Prazeres da Costa, Clarissa (Author) , Vanes, Lesley (Author) , Kumar, Vinod (Author) , Johnson, Melissa (Author) , Menacho-Márquez, Mauricio (Author) , Habermann, Bianca (Author) , Tybulewicz, Victor L. (Author) , Netea, Mihai (Author) , Bustelo, Xosé R. (Author) , Ruland, Jürgen (Author)
Format: Article (Journal)
Language:English
Published: December 6, 2016
In: Cell reports
Year: 2016, Volume: 17, Issue: 10, Pages: 2572-2583
ISSN:2211-1247
DOI:10.1016/j.celrep.2016.11.018
Online Access:Resolving-System, lizenzpflichtig, Volltext: https://doi.org/10.1016/j.celrep.2016.11.018
Verlag, lizenzpflichtig, Volltext: http://www.sciencedirect.com/science/article/pii/S2211124716315741
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Author Notes:Susanne 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 L. Tybulewicz, Mihai Netea, Xosé R. Bustelo, and Jürgen Ruland
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Summary: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.
Item Description:Gesehen am 05.05.2020
Physical Description:Online Resource
ISSN:2211-1247
DOI:10.1016/j.celrep.2016.11.018

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