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

Abstract

SummaryFungal 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.

Antifungal Innate Immunity: A Perspective from the Last 10 Years

“…The authors showed that treatment strategies involving the inhibition of CBLB led to increased inflammatory responses and improved the outcome of experimental candidiasis, which provides evidence that CBLB might represent a therapeutic target in fungal disease. Furthermore, it has been found that another ubiquitin ligase TRIM62 as well as Vav proteins regulate CARD9-mediated antifungal immunity, and these molecules are also potential therapeutic targets [10, 11]. Vav proteins are key activators of the CARD9 pathway by cooperating downstream of dectin-1 to engage CARD9 for NF-κB control and proinflammatory gene transcription, while TRIM62 acts as a CARD9-binding partner facilitating CARD9 poly­ubiquitination, which is essential for its activity.…”

“…Vav proteins are key activators of the CARD9 pathway by cooperating downstream of dectin-1 to engage CARD9 for NF-κB control and proinflammatory gene transcription, while TRIM62 acts as a CARD9-binding partner facilitating CARD9 poly­ubiquitination, which is essential for its activity. Moreover, TRIM62- as well as Vav1/2/3-deficient mice exhibit extreme susceptibility to Candida infection, suggesting that they have a pivotal role in antifungal immunity [10, 11]. Interestingly, CD23, a novel CLR, which is well known for its function as a low-affinity receptor for IgE, plays an important role in antifungal immunity through recognition of surface components of fungal pathogens, such as α-mannan and β-glucan, leading to upregulation of nitric oxide synthase (NOS2) expression, reactive oxygen species (ROS) production, and fungal killing.…”

A minimal RNA ligand for potent RIG-I activation in living mice

“…5 and SUPP. Table 2) (40)(41)(42). A divergent noncoding transcript (9130024F11Rik) that shares a promoter with SATB2 is also highly upregulated (SUPP.…”

The CARD-CC/Bcl10/paracaspase signaling complex is functionally conserved since the last common ancestor of Planulozoa

“…Interestingly, a survey of invertebrate Dectin-1 C-lectin domain homologs finds back top-scoring hits from mollusks and cnidarians but not the much better characterized arthropod and nematode genomes (Pees et al 2016), similar to previous observations (Wood-Charlson and Weis 2009). Recently, the vav1-3 proteins were found to be critical for CARD9 signaling downstream of lectin receptors (Roth et al 2016), and also these proteins are more similar in cnidarians and lophotrochozoans compared to other invertebrates. C-type lectins are already associated to innate immunity in mollusks and cnidarians (Vidal-Dupiol et al 2009).…”