title: Vav Proteins Are Key Regulators of Card9 Signaling for Innate Antifungal Immunity.
abstract: 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.
authors.affiliation: Institut für Klinische Chemie und Pathobiochemie, Klinikum rechts der Isar, Technische Universität München, 81675 München, Germany; Chirurgische Klinik, Universitätsklinikum Heidelberg, Ruprecht-Karls-Universität, 69120 Heidelberg, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Roth
authors.affiliation: Institut für Klinische Chemie und Pathobiochemie, Klinikum rechts der Isar, Technische Universität München, 81675 München, Germany.
authors.forename: Hanna
authors.initials: H
authors.lastname: Bergmann
authors.affiliation: Department of Medicine, Radboud University, Medical Centre, 6500 HB Nijmegen, the Netherlands; Radboud Center for Infectious Diseases, 6500 HB Nijmegen, the Netherlands.
authors.forename: Martin
authors.initials: M
authors.lastname: Jaeger
authors.affiliation: Max Planck Institute of Biochemistry, Research Group Computational Biology, 82152 Martinsried, Germany.
authors.forename: Assa
authors.initials: A
authors.lastname: Yeroslaviz
authors.affiliation: Institut für Klinische Chemie und Pathobiochemie, Klinikum rechts der Isar, Technische Universität München, 81675 München, Germany.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Neumann
authors.affiliation: Institut für Klinische Chemie und Pathobiochemie, Klinikum rechts der Isar, Technische Universität München, 81675 München, Germany.
authors.forename: Paul-Albert
authors.initials: PA
authors.lastname: Koenig
authors.affiliation: Institut für Medizinische Mikrobiologie, Immunologie, und Hygiene, Klinikum rechts der Isar, Technische Universität München, 81675 München, Germany.
authors.forename: Clarissa
authors.initials: C
authors.lastname: Prazeres da Costa
authors.affiliation: Francis Crick Institute, London NW1 1AT, UK.
authors.forename: Lesley
authors.initials: L
authors.lastname: Vanes
authors.affiliation: Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, 9700 RB, the Netherlands.
authors.forename: Vinod
authors.initials: V
authors.lastname: Kumar
authors.affiliation: Duke University Medical Center, Duke Box 102359, Durham, NC 27710, USA.
authors.forename: Melissa
authors.initials: M
authors.lastname: Johnson
authors.affiliation: Centro de Investigación del Cáncer, CSIC-University of Salamanca, 37007 Salamanca, Spain.
authors.forename: Mauricio
authors.initials: M
authors.lastname: Menacho-Márquez
authors.affiliation: Max Planck Institute of Biochemistry, Research Group Computational Biology, 82152 Martinsried, Germany.
authors.forename: Bianca
authors.initials: B
authors.lastname: Habermann
authors.affiliation: Francis Crick Institute, London NW1 1AT, UK; Department of Medicine, Imperial College, London W12 0NN, UK.
authors.forename: Victor L
authors.initials: VL
authors.lastname: Tybulewicz
authors.affiliation: Department of Medicine, Radboud University, Medical Centre, 6500 HB Nijmegen, the Netherlands.
authors.forename: Mihai
authors.initials: M
authors.lastname: Netea
authors.affiliation: Centro de Investigación del Cáncer, CSIC-University of Salamanca, 37007 Salamanca, Spain; Centro de Investigacion Biomedica en Red-Oncologia, Carlos III Health Institute, Spain.
authors.forename: Xosé R
authors.initials: XR
authors.lastname: Bustelo
authors.affiliation: Institut für Klinische Chemie und Pathobiochemie, Klinikum rechts der Isar, Technische Universität München, 81675 München, Germany; German Cancer Consortium (DKTK), 69120 Heidelberg, Germany; German Center for Infection Research (DZIF), Partner Site Munich, Munich, Germany. Electronic address: j.ruland@tum.de.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Ruland
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage; D053468:CARD Signaling Adaptor Proteins / Q000235:genetics* / Q000378:metabolism; D002175:Candida / Q000235:genetics / Q000378:metabolism* / Q000472:pathogenicity; D058387:Candidemia / Q000235:genetics* / Q000382:microbiology / Q000473:pathology; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics*; D037181:Lectins, C-Type / Q000235:genetics* / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D051567:Proto-Oncogene Proteins c-vav / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D000099181:Dectin-1
chemical_list: D000935:Antifungal Agents; D053468:CARD Signaling Adaptor Proteins; D037181:Lectins, C-Type; D008565:Membrane Proteins; D016328:NF-kappa B; D051567:Proto-Oncogene Proteins c-vav; D000099181:Dectin-1; C513280:Card9 protein, mouse; C113583:Clecsf8 protein, mouse; C496619:Vav1 protein, mouse; C490565:Vav2 protein, mouse; C496622:Vav3 protein, mouse; C445340:dectin-2, mouse