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| Status |
Public on Feb 10, 2017 |
| Title |
Vav proteins are key regulators of Card9 signaling for innate antifungal immunity |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
Fungal infections are major causes of morbidity and mortality, especially in immunocompromised individuals. The innate immune system senses fungal pathogens through a family of Syk-coupled C-type lectin receptors (CLRs), which signal through the conserved immune adapter Card9. Although Card9 complexes are essential for antifungal defense in humans and mice, the mechanisms that couple CLR-proximal events to Card9 control are not well defined. Here, using a proteomic approach, we identified Vav proteins as key activators of the Card9 pathway. Vav1, Vav2 and Vav3 cooperate downstream of Dectin-1, Dectin-2 and Mincle to selectively engage Card9 for NF-κB control and proinflammatory gene transcription but are not involved in MAPK activation. Although Vav family members show functional redundancy, Vav1/2/3 triple-deficient cells are severely impaired for NF-κB and cytokine responses upon stimulation with CLR agonists or hyphae, and Vav1/2/3-/- mice phenocopy Card9-/- animals with extreme susceptibility to fungi and rapid mortality upon Candida albicans infection. 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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| Overall design |
RNA profiles of unstimulated or Curdlan-stimulated bone marrow-derived dendritic cells (BMDCs) from wild type (WT) and Vav1/2/3-/- (VAV KO) mice were generated by deep sequencing, in triplicate, using Illumina HiSeq 2000.
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| |
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| Contributor(s) |
Ruland J, Roth S, Yeroslaviz A |
| Citation(s) |
27926862 |
| |
| Submission date |
Jun 27, 2016 |
| Last update date |
May 15, 2019 |
| Contact name |
Assa Yeroslaviz |
| E-mail(s) |
yeroslaviz@biochem.mpg.de
|
| Organization name |
Max-Planck-Institute for biochemistry
|
| Department |
computational Biology
|
| Street address |
Am Klopferspitz 18
|
| City |
Martinsried |
| State/province |
Bavaria |
| ZIP/Postal code |
82152 |
| Country |
Germany |
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| Platforms (1) |
| GPL13112 |
Illumina HiSeq 2000 (Mus musculus) |
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| Samples (12)
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| Relations |
| BioProject |
PRJNA326900 |
| SRA |
SRP077255 |
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