Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

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 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE83736 | GEO | 2017/02/10

SECONDARY ACCESSION(S): PRJNA326900

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

The protective effect of inflammatory monocytes during systemic C. albicans infection is dependent on collaboration between C-type lectin-like receptors

Project description:Invasive candidiasis, mainly caused by Candida albicans, is a serious healthcare problem with high mortality rates, particularly in immunocompromised patients. Innate immune cells express pathogen recognition receptors (PRRs) including C-type lectin-like receptors (CLRs) that bind C. albicans to initiate an immune response. Multiple CLRs including Dectin-1, Dectin-2 and Mincle have been proposed individually to contribute to the immune response to C. albicans. However how these receptors collaborate to clear a fungal infection is unknown. Herein, we used novel multi-CLR knockout (KO) mice to decipher the individual, collaborative and collective roles of Dectin-1, Dectin-2 and Mincle during systemic C. albicans infection. These studies revealed an unappreciated and profound role for CLR co-operation in anti-fungal immunity. The protective effect of multiple CLRs was markedly greater than any single receptor, and was mediated through inflammatory monocytes via recognition and phagocytosis of C. albicans, and production of C. albicans-induced cytokines and chemokines. These CLRs were dispensable for mediating similar responses from neutrophils, likely due to lower expression of these CLRs on neutrophils compared to inflammatory monocytes. Concurrent deletion of Dectin-1 and Dectin-2, or all three CLRs, resulted in dramatically increased susceptibility to systemic C. albicans infection compared to mice lacking a single CLR. Multi-CLR KO mice were unable to control fungal growth due to an inadequate early inflammatory monocyte-mediated response. In response to excessive fungal growth, the multi-CLR KO mice mounted a hyper-inflammatory response, likely leading to multiple organ failure. Thus, these data reveal a critical role for CLR co-operation in the effective control of C. albicans and maintenance of organ function during infection.

2019-06-20 | E-MTAB-8030 | biostudies-arrayexpress

VAV3 in ERBB4-mediated cancer cell migration

Project description:ERBB4 is a member of the epidermal growth factor receptor (EGFR)/ERBB subfamily of receptor tyrosine kinases that regulates cellular processes including proliferation, migration and survival. ERBB4 signaling is involved in embryogenesis and homeostasis of adult tissues, but also in human pathologies such as cancer, neurological disorders and cardiovascular diseases. A mass spectrometry screen revealed guanine nucleotide exchange factor (GEF) VAV3, an activator of Rho family GTPases, as a novel ERBB4-interacting protein in breast cancer cells. The ERBB4-VAV3-interaction was confirmed by targeted mass-spectrometry, coimmunoprecipitation experiments, and further defined by demonstrating that kinase activity and tyrosine residues 1022 and 1162 of ERBB4, as well as the intact phosphotyrosine-interacting SH2 domain of VAV3 were necessary for the interaction. ERBB4 was also shown to stimulate tyrosine phosphorylation of the VAV3 activation domain, which is required for GEF activity of VAV proteins. In addition to VAV3, also the other members of the VAV family, VAV1 and VAV2 were shown to coprecipitate with ERBB4. Analyses of the effects of overexpression of dominant-negative VAV3 constructs or downregulation of VAV3 expression by shRNAs in breast cancer cells demonstrated that active VAV3 was involved in ERBB4-stimulated migration. These findings define the VAV GTPases as novel effectors of ERBB4 activity in a signaling pathway relevant for cancer cell migration.

2020-06-24 | PXD019430 | Pride

Genome-wide analysis of the CARD9/Dectin-1 transcriptional program in neutrophils and macrophages by RNA-seq

Project description:Purpose: To characterize Card9-dependent and Card9-independent Dectin-1 mediated gene expression changes in neutrophils and to compare response to Dectin-1 stimulation in neutrophils and macrophages. Method: BM neutrophils from WT and Card9-/- mice were isolated by MACS column purification and treated with or without the Dectin-1 agonist, curdlan for 3 hrs. WT BM-derived macrophages were also treated with or without curdlan for 3hrs before sample collection. Results: We identified both Card9-dependent and Card9-independent gene expression changes with Dectin-1 stimulation in neutrophils. We also identified cell-type specific differences in the response to Dectin-1 stimulation in neutrophils and macrophages. Conclusions: Dectin-1 stimulation induces significant gene expression changes regulated by either canonical Card9-dependent or non-canonical Card9-independent mechanisms.

2021-02-26 | GSE148850 | GEO

in vitro ubiquitination by E3 ligase Cbl-b

Project description:Fungal infections claim an estimated 1.5 million lives every year. Mechanisms that protect from fungal infections are still elusive. Recognition of fungal pathogens relies on C-type lectin receptors (CLR) and their downstream signaling kinase SYK. Here we report that the E3-ubiquitin-ligase CBL-B controls proximal C-type lectin receptor signaling in macrophages and dendritic cells. We show that CBL-B associates with SYK and ubiquitinates SYK, Dectin-1, and Dectin-2 upon fungal recognition. Functionally, CBL-B deficiency results in increased inflammasome activation, enhanced reactive oxygen species production, and increased fungal killing. Genetic deletion of Cblb protects mice from morbidity caused by cutaneous infection and markedly improves survival upon a lethal systemic infection with Candida albicans. Based on these findings, we engineered a cell-permeable CBL-B inhibitory peptide that protects mice from lethal C. albicans infections. We thus describe a key role for Cblb in the regulation of innate anti-fungal immunity and establish a novel paradigm for the treatment of fungal sepsis.

2016-06-17 | PXD004256 | Pride

Genome-wide analysis of gene expression in VAV1-/- versus VAV1+/+ bone marrow (BM)-macrophages

Project description:Analysis of differential gene expression profiles in VAV1-/- versus VAV+/+ BM-macrophages , respectively. A distinct expression profile in VAV1-/- versus VAV1+/+ (wild-type) BM-macrophages allows to resolve molecular mechanisms.

2013-03-08 | GSE36123 | GEO

Gene expression in bone marrow-derived dendritic cells obtained from wild-type mice or 3BP2 DL/DL mice stimulated with or without curdlan

Project description:C-type lectin dectin-1 is known to recognize beta-glucans such as curdlan and propagate intracellular signaling for activation of NF-kappa B to induce anti-fungal immunity. Recently, we found that adaptor protein 3BP2 is required for the dectin-1-induced activation of NF-kappa B. In this study, we performed microarray analysis to identify genes of which expression is regulated by dectin-1 and 3BP2.

2024-11-15 | GSE263167 | GEO

Genome-wide analysis of gene expression in VAV1-/- versus VAV1+/+ bone marrow (BM)-macrophages

2013-03-08 | E-GEOD-36123 | biostudies-arrayexpress

Pathogen size alters C-type lectin receptor signaling in dendritic cells to influence CD4 Th9 cell differentiation

Project description:Dectin-1 recognizes β-glucan in fungal cell walls, and activation of Dectin-1 in dendritic cells (DCs) influences immune responses against fungi. Although many studies have shown that Dectin-1 activated DCs induce different subsets of T helper cells according to different cytokine milieus, the precise mechanisms underlying such differences remain unknown. By harnessing polymorphic Candida albicans and polystyrene beads of different sizes, we found that target size influences production of cytokine that control differentiation of T helper cell subsets. Hyphal C. albicans and large beads activate DCs but cannot be phagocytosed due to their size, which prolongs the duration of Dectin-1 signaling. Transcriptomic analysis revealed that the expression of Il33 was significantly increased by larger targets, and increased IL-33 expression promoted TH9 responses. Expression of IL-33 was regulated by Dectin-1-SYK-PLCγ-CARD9-ERK pathway. Altogether, our study demonstrates that size of fungi can be a determining factor in which DCs induce context-appropriate adaptive immune responses.

2022-04-01 | GSE181734 | GEO

BLNK negatively regulates C-type lectin receptor-mediated antifungal immunity through inhibiting macrophage migration

Project description:B cell linker protein (BLNK) is a pivotal adaptor protein that interfaces the B cell receptor (BCR)-associated spleen tyrosine kinase (Syk) to regulate B cell function and development. However, it is still not well understood whether BLNK is involved in Syk-coupled C-type lectin receptor (CLR) signaling in myeloid cells, particularly in the context of antifungal immunity. Here, we show that stimulation with fungi-derived β-glucans or α-mannans induced the phosphorylation of BLNK in macrophages, which was significantly impaired due to the deficiency of CLRs including Dectin-1 and Dectin-2, as well as their downstream mediators Syk and Fc-receptor gamma-chain (FcRγ). Furthermore, BLNK is induced to be interacted with casitas B-lineage lymphoma (c-Cbl), which is completely dependent on the engagement of Dectin-1 and Dectin-2. Notably, BLNK deficiency facilitates CLR-mediated recruitment of c-Cbl/phosphatidylinositol 3-kinase (PI3K) complex to F-actin cytoskeleton, thereby promoting macrophage migration. Consequently, mice with monocyte-specific deficiency of BLNK are highly resistant to the infection with Candida albicans, a major human fungal pathogen, through increasing the infiltration of Ly6C+macrophages into kidneys. Together, our data indicate that BLNK functions downstream of Syk-coupled CLRs to negatively regulate antifungal immunity against C. albicans infection. These findings unravel a previously unidentified role of BLNK that negatively regulates macrophage migration through inhibiting CLR-mediated recruitment of c-Cbl/PI3K complex to the cytoskeleton.

2023-11-07 | GSE246891 | GEO

in vitro ubiquitination by E3 ligase Cbl-b

2017-03-29 | MSV000080745 | MassIVE