A2AIV8 · CARD9_MOUSE

  • Protein
    Caspase recruitment domain-containing protein 9
  • Gene
    Card9
  • Status
    UniProtKB reviewed (Swiss-Prot)
  • Amino acids
  • Protein existence
    Evidence at protein level
  • Annotation score
    5/5

Function

function

Adapter protein that plays a key role in innate immune response against fungi by forming signaling complexes downstream of C-type lectin receptors (PubMed:16862125, PubMed:20538615, PubMed:26679537, PubMed:29080677).
CARD9-mediated signals are essential for antifungal immunity against a subset of fungi from the phylum Ascomycota (PubMed:16862125, PubMed:20538615, PubMed:24470469, PubMed:25621893, PubMed:26679537, PubMed:29080677, PubMed:32548948).
Transduces signals in myeloid cells downstream of C-type lectin receptors CLEC7A (dectin-1), CLEC6A (dectin-2) and CLEC4E (Mincle), which detect pathogen-associated molecular pattern metabolites (PAMPs), such as fungal carbohydrates, and trigger CARD9 activation (PubMed:16862125, PubMed:20538615).
Upon activation, CARD9 homooligomerizes to form a nucleating helical template that recruits BCL10 via CARD-CARD interaction, thereby promoting polymerization of BCL10 and subsequent recruitment of MALT1: this leads to activation of NF-kappa-B and MAP kinase p38 (MAPK11, MAPK12, MAPK13 and/or MAPK14) pathways which stimulate expression of genes encoding pro-inflammatory cytokines and chemokines (PubMed:16862125, PubMed:20538615, PubMed:22265677, PubMed:29080677).
CARD9 signaling in antigen-presenting cells links innate sensing of fungi to the activation of adaptive immunity and provides a cytokine milieu that induces the development and subsequent of interleukin 17-producing T helper (Th17) cells (PubMed:17450144, PubMed:24470469, PubMed:32358020).
Also involved in activation of myeloid cells via classical ITAM-associated receptors and TLR: required for TLR-mediated activation of MAPK, while it is not required for TLR-induced activation of NF-kappa-B (PubMed:17486093).
CARD9 can also be engaged independently of BCL10: forms a complex with RASGRF1 downstream of C-type lectin receptors, which recruits and activates HRAS, leading to ERK activation and the production of cytokines (PubMed:25267792).
Acts as an important regulator of the intestinal commensal fungi (mycobiota) component of the gut microbiota (PubMed:27158904, PubMed:33548172).
Plays an essential role in antifungal immunity against dissemination of gut fungi: acts by promoting induction of antifungal IgG antibodies response in CX3CR1+ macrophages to confer protection against disseminated C.albicans or C.auris infection (PubMed:33548172).
Also mediates immunity against other pathogens, such as certain bacteria, viruses and parasites; CARD9 signaling is however redundant with other innate immune responses (PubMed:17187069, PubMed:26679537, PubMed:29080677).
In response to L.monocytogenes infection, required for the production of inflammatory cytokines activated by intracellular peptidoglycan: acts by connecting NOD2 recognition of peptidoglycan to downstream activation of MAP kinases (MAPK) without activating NF-kappa-B (PubMed:17187069).

Activity regulation

Maintained in an autoinhibited state via homodimerization in which the CARD domain forms an extensive interaction with the adjacent linker and coiled-coil regions (By similarity).
Activation downstream of C-type lectin receptors, by phosphorylation by PRKCD and/or ubiquitination by TRIM62, triggers disruption of the CARD domain-coiled coil interface, CARD9 homooligomerization and BCL10 recruitment, followed by activation of NF-kappa-B and MAP kinase p38 pathways (PubMed:22265677).
Zinc-binding inhibits activation by stabilizing the CARD ground-state conformation and restricting its capacity to form BCL10-nucleating filaments (By similarity).

Features

Showing features for binding site.

TypeIDPosition(s)Description
Binding site3Zn2+ (UniProtKB | ChEBI)
Binding site10Zn2+ (UniProtKB | ChEBI)
Binding site73Zn2+ (UniProtKB | ChEBI)

GO annotations

AspectTerm
Cellular ComponentCBM complex
Cellular Componentcytoplasm
Cellular Componentcytosol
Molecular FunctionCARD domain binding
Molecular Functionmetal ion binding
Molecular Functionprotein homodimerization activity
Biological Processantifungal innate immune response
Biological Processdefense response to Gram-positive bacterium
Biological Processdefense response to virus
Biological Processhost-mediated regulation of intestinal microbiota composition
Biological Processimmunoglobulin mediated immune response
Biological ProcessJNK cascade
Biological Processneutrophil mediated immunity
Biological Processpositive regulation of canonical NF-kappaB signal transduction
Biological Processpositive regulation of chemokine production
Biological Processpositive regulation of cytokine production
Biological Processpositive regulation of cytokine production involved in inflammatory response
Biological Processpositive regulation of ERK1 and ERK2 cascade
Biological Processpositive regulation of granulocyte macrophage colony-stimulating factor production
Biological Processpositive regulation of innate immune response
Biological Processpositive regulation of interleukin-17 production
Biological Processpositive regulation of interleukin-6 production
Biological Processpositive regulation of JNK cascade
Biological Processpositive regulation of macrophage cytokine production
Biological Processpositive regulation of NF-kappaB transcription factor activity
Biological Processpositive regulation of stress-activated MAPK cascade
Biological Processpositive regulation of T-helper 17 type immune response
Biological Processpositive regulation of tumor necrosis factor production
Biological Processprotein homooligomerization
Biological Processregulation of apoptotic process
Biological Processregulation of interleukin-2 production
Biological Processregulation of interleukin-6 production
Biological Processregulation of tumor necrosis factor production
Biological Processresponse to aldosterone
Biological Processresponse to exogenous dsRNA
Biological Processresponse to fungus
Biological Processresponse to muramyl dipeptide
Biological Processresponse to peptidoglycan
Biological Processresponse to xenobiotic stimulus
Biological Processstress-activated MAPK cascade

Keywords

Enzyme and pathway databases

Names & Taxonomy

Protein names

  • Recommended name
    Caspase recruitment domain-containing protein 9

Gene names

    • Name
      Card9

Organism names

  • Taxonomic identifier
  • Strain
    • C57BL/6J
  • Taxonomic lineage
    Eukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Euarchontoglires > Glires > Rodentia > Myomorpha > Muroidea > Muridae > Murinae > Mus > Mus

Accessions

  • Primary accession
    A2AIV8

Proteomes

Organism-specific databases

Subcellular Location

Keywords

Phenotypes & Variants

Disruption phenotype

Mice were born at the normal Mendelian ratio without obvious anatomical defects but display impaired innate immunity (PubMed:16862125, PubMed:17187069).
In response to C.albicans infection, mice develop fungal infections, many of which target the central nervous system (CNS) (PubMed:26679537).
All mice die within 5 days after infection by C.albicans whereas more than half of the control mice survive for more than 12 days (PubMed:16862125).
Impaired zymosan-induced cytokine production (PubMed:16862125).
No defects in adaptive immunity (PubMed:16862125).
Mice show impaired recruitment of neutrophils in CNS after infection by C.albicans, an immune cell critical for antifungal host defense (PubMed:26679537).
Mice are susceptible to pulmonary infection with C.neoformans and show decreased Th17-related immune response (PubMed:24470469).
Mice are highly susceptible to phaeohyphomycosis following E.spinifera infection and show impaired antifungal immunity, characterized by reduced cytokine production and neutrophil recruitment (PubMed:29080677).
Mice are susceptible to A.fumigatus and P.pneumonia infection (PubMed:25621893, PubMed:32548948).
Mice are more susceptible to colitis and have an increased load of gut-resident fungi (mycobiota), causing gut fungal dysbiosis (PubMed:23732773, PubMed:27158904).
Mice are unable to induce an efficient IgG antibody response against disseminated C.albicans infection (PubMed:33548172).
Following infection by L.monocytogenes, mice fail to clear infection and show altered cytokine production (PubMed:17187069).

Features

Showing features for mutagenesis.

TypeIDPosition(s)Description
Mutagenesis231Reduced phosphorylation by PKC/PRKCD, leading to impaired interaction with BCL10 and decreased activation of NF-kappa-B and MAP kinase p38 pathways.
Mutagenesis303Does not affect phosphorylation by PKC/PRKCD.

Variants

We now provide the "Disease & Variants" viewer in its own tab.

The viewer provides 22 variants from UniProt as well as other sources including ClinVar and dbSNP.

Go to variant viewer

PTM/Processing

Features

Showing features for chain, modified residue, cross-link.

TypeIDPosition(s)Description
ChainPRO_00004287251-536Caspase recruitment domain-containing protein 9
Modified residue2Phosphoserine
Cross-link125Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)
Modified residue231Phosphothreonine; by PKC/PRKCD
Modified residue277Phosphoserine
Modified residue424Phosphoserine
Modified residue425Phosphoserine
Modified residue431Phosphoserine
Modified residue451Phosphoserine
Modified residue461Phosphoserine
Modified residue483Phosphoserine
Modified residue498Phosphoserine
Modified residue531Phosphothreonine; by CK2
Modified residue533Phosphothreonine; by CK2

Post-translational modification

Phosphorylated at Thr-231 by PRKCD downstream of C-type lectin receptors activation: phosphorylation promotes interaction with BCL10, followed by activation of NF-kappa-B and MAP kinase p38 pathways (PubMed:22265677).
Phosphorylated at Thr-531 and Thr-531 by CK2 following interaction with VHL, leading to inhibit the ability to activate NF-kappa-B (By similarity).
Ubiquitinated at Lys-125 via 'Lys-27'-linked ubiquitin by TRIM62 downstream of C-type lectin receptors activation; leading to CARD9 activation, followed by activation of NF-kappa-B and MAP kinase p38 pathways (By similarity).
Deubiquitinated at Lys-125 by USP15, inhibiting CARD9 (By similarity).

Keywords

Proteomic databases

PTM databases

Expression

Tissue specificity

Specifically expressed in myeloid cells (PubMed:16862125, PubMed:17187069).
Not expressed in non-lymphoid organs (PubMed:16862125, PubMed:17187069).

Gene expression databases

Interaction

Subunit

Monomer (By similarity).
Homodimer; homodimerization is mediated by the CARD domain which forms an extensive interaction with the adjacent linker and coiled-coil regions; leads to an autoinhibited state (By similarity).
Homomultimer; polymerizes following activation, forming a nucleating helical template that seeds BCL10-filament formation via a CARD-CARD interaction (By similarity).
Interacts (via CARD domain) with BCL10 (via CARD domain); interaction takes place following CARD9 activation and polymerization, leading to the formation of a filamentous CBM complex assembly (PubMed:22265677).
Component of a CBM complex (CARD9-BCL10, MALT1), composed of CARD9, BCL10 and MALT1 (PubMed:22265677).
Interacts with RASGRF1 (By similarity).
Interacts with NOD2 (via NACHT domain); interaction is direct (PubMed:17187069, PubMed:24960071).
Interacts with RIPK2 (PubMed:17187069).
Interacts with VHL; without leading to protein degradation (By similarity).

Protein-protein interaction databases

Miscellaneous

Structure

Family & Domains

Features

Showing features for domain, region, coiled coil, compositional bias.

TypeIDPosition(s)Description
Domain6-98CARD
Region99-116Linker
Coiled coil117-272
Coiled coil303-415
Compositional bias425-442Polar residues
Region425-451Disordered
Region476-536Disordered
Compositional bias485-507Basic and acidic residues
Compositional bias517-536Polar residues

Domain

The linker region, also named autoinhibitory interface, is required to prevent constitutive activation and maintain CARD9 in an autoinhibitory state. Disruption of this region triggers polymerization and activation, leading to formation of BCL10-nucleating filaments.

Keywords

Phylogenomic databases

Family and domain databases

Sequence

  • Sequence status
    Complete
  • Length
    536
  • Mass (Da)
    62,462
  • Last updated
    2007-02-20 v1
  • Checksum
    3A5403C7A04EA2C9
MSDYENDDECWSTLESFRVKLISVIDPSRITPYLRQCKVLNPDDEEQVLSDPNLVIRKRKVGVLLDILQRTGHKGYVAFLESLELYYPQLYRKVTGKEPARVFSMIIDASGESGLTQLLMTEVMKLQKKVQDLTALLSSKDDFIKELRVKDSLLRKHQERVQRLKEECELSSAELKRCKDENYELAMCLAHLSEEKGAALMRNRDLQLEVDRLRHSLMKAEDDCKVERKHTLKLRHAMEQRPSQELLWELQQEKDLLQARVQELQVSVQEGKLDRNSPYIQVLEEDWRQALQEHQKQVSTIFSLRKDLRQAETLRARCTEEKEMFELQCLALRKDAKMYKDRIEAILLQMEEVSIERDQAMASREELHAQCTQSFQDKDKLRKLVRELGEKADELQLQLFQTESRLLAAEGRLKQQQLDMLILSSDLEDSSPRNSQELSLPQDLEEDAQLSDKGVLADRESPEQPFMALNKEHLSLTHGMGPSSSEPPEKERRRLKESFENYRRKRALRKMQNSWRQGEGDRGNTTGSDNTDTEGS

Features

Showing features for compositional bias.

TypeIDPosition(s)Description
Compositional bias425-442Polar residues
Compositional bias485-507Basic and acidic residues
Compositional bias517-536Polar residues

Keywords

Sequence databases

Nucleotide SequenceProtein SequenceMolecule TypeStatus
AL732541
EMBL· GenBank· DDBJ
-Genomic DNA No translation available.
BC151023
EMBL· GenBank· DDBJ
AAI51024.1
EMBL· GenBank· DDBJ
mRNA

Genome annotation databases

Similar Proteins

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