A2AIV8 · CARD9_MOUSE
- ProteinCaspase recruitment domain-containing protein 9
- GeneCard9
- StatusUniProtKB reviewed (Swiss-Prot)
- Organism
- Amino acids536 (go to sequence)
- Protein existenceEvidence at protein level
- Annotation score5/5
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).
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).
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.
GO annotations
Keywords
- Biological process
- Ligand
Enzyme and pathway databases
Names & Taxonomy
Protein names
- Recommended nameCaspase recruitment domain-containing protein 9
Gene names
Organism names
- Organism
- Strain
- Taxonomic lineageEukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Euarchontoglires > Glires > Rodentia > Myomorpha > Muroidea > Muridae > Murinae > Mus > Mus
Accessions
- Primary accessionA2AIV8
Proteomes
Organism-specific databases
Subcellular Location
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).
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.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Mutagenesis | 231 | Reduced phosphorylation by PKC/PRKCD, leading to impaired interaction with BCL10 and decreased activation of NF-kappa-B and MAP kinase p38 pathways. | ||||
Sequence: T → A | ||||||
Mutagenesis | 303 | Does not affect phosphorylation by PKC/PRKCD. | ||||
Sequence: S → A |
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.
PTM/Processing
Features
Showing features for chain, modified residue, cross-link.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Chain | PRO_0000428725 | 1-536 | Caspase recruitment domain-containing protein 9 | |||
Sequence: MSDYENDDECWSTLESFRVKLISVIDPSRITPYLRQCKVLNPDDEEQVLSDPNLVIRKRKVGVLLDILQRTGHKGYVAFLESLELYYPQLYRKVTGKEPARVFSMIIDASGESGLTQLLMTEVMKLQKKVQDLTALLSSKDDFIKELRVKDSLLRKHQERVQRLKEECELSSAELKRCKDENYELAMCLAHLSEEKGAALMRNRDLQLEVDRLRHSLMKAEDDCKVERKHTLKLRHAMEQRPSQELLWELQQEKDLLQARVQELQVSVQEGKLDRNSPYIQVLEEDWRQALQEHQKQVSTIFSLRKDLRQAETLRARCTEEKEMFELQCLALRKDAKMYKDRIEAILLQMEEVSIERDQAMASREELHAQCTQSFQDKDKLRKLVRELGEKADELQLQLFQTESRLLAAEGRLKQQQLDMLILSSDLEDSSPRNSQELSLPQDLEEDAQLSDKGVLADRESPEQPFMALNKEHLSLTHGMGPSSSEPPEKERRRLKESFENYRRKRALRKMQNSWRQGEGDRGNTTGSDNTDTEGS | ||||||
Modified residue | 2 | Phosphoserine | ||||
Sequence: S | ||||||
Cross-link | 125 | Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) | ||||
Sequence: K | ||||||
Modified residue | 231 | Phosphothreonine; by PKC/PRKCD | ||||
Sequence: T | ||||||
Modified residue | 277 | Phosphoserine | ||||
Sequence: S | ||||||
Modified residue | 424 | Phosphoserine | ||||
Sequence: S | ||||||
Modified residue | 425 | Phosphoserine | ||||
Sequence: S | ||||||
Modified residue | 431 | Phosphoserine | ||||
Sequence: S | ||||||
Modified residue | 451 | Phosphoserine | ||||
Sequence: S | ||||||
Modified residue | 461 | Phosphoserine | ||||
Sequence: S | ||||||
Modified residue | 483 | Phosphoserine | ||||
Sequence: S | ||||||
Modified residue | 498 | Phosphoserine | ||||
Sequence: S | ||||||
Modified residue | 531 | Phosphothreonine; by CK2 | ||||
Sequence: T | ||||||
Modified residue | 533 | Phosphothreonine; by CK2 | ||||
Sequence: T |
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).
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).
Deubiquitinated at Lys-125 by USP15, inhibiting CARD9 (By similarity).
Keywords
- PTM
Proteomic databases
PTM 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).
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.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Domain | 6-98 | CARD | ||||
Sequence: NDDECWSTLESFRVKLISVIDPSRITPYLRQCKVLNPDDEEQVLSDPNLVIRKRKVGVLLDILQRTGHKGYVAFLESLELYYPQLYRKVTGKE | ||||||
Region | 99-116 | Linker | ||||
Sequence: PARVFSMIIDASGESGLT | ||||||
Coiled coil | 117-272 | |||||
Sequence: QLLMTEVMKLQKKVQDLTALLSSKDDFIKELRVKDSLLRKHQERVQRLKEECELSSAELKRCKDENYELAMCLAHLSEEKGAALMRNRDLQLEVDRLRHSLMKAEDDCKVERKHTLKLRHAMEQRPSQELLWELQQEKDLLQARVQELQVSVQEGK | ||||||
Coiled coil | 303-415 | |||||
Sequence: SLRKDLRQAETLRARCTEEKEMFELQCLALRKDAKMYKDRIEAILLQMEEVSIERDQAMASREELHAQCTQSFQDKDKLRKLVRELGEKADELQLQLFQTESRLLAAEGRLKQ | ||||||
Compositional bias | 425-442 | Polar residues | ||||
Sequence: SDLEDSSPRNSQELSLPQ | ||||||
Region | 425-451 | Disordered | ||||
Sequence: SDLEDSSPRNSQELSLPQDLEEDAQLS | ||||||
Region | 476-536 | Disordered | ||||
Sequence: LTHGMGPSSSEPPEKERRRLKESFENYRRKRALRKMQNSWRQGEGDRGNTTGSDNTDTEGS | ||||||
Compositional bias | 485-507 | Basic and acidic residues | ||||
Sequence: SEPPEKERRRLKESFENYRRKRA | ||||||
Compositional bias | 517-536 | Polar residues | ||||
Sequence: QGEGDRGNTTGSDNTDTEGS |
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
- Domain
Phylogenomic databases
Family and domain databases
Sequence
- Sequence statusComplete
- Length536
- Mass (Da)62,462
- Last updated2007-02-20 v1
- Checksum3A5403C7A04EA2C9
Features
Showing features for compositional bias.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Compositional bias | 425-442 | Polar residues | ||||
Sequence: SDLEDSSPRNSQELSLPQ | ||||||
Compositional bias | 485-507 | Basic and acidic residues | ||||
Sequence: SEPPEKERRRLKESFENYRRKRA | ||||||
Compositional bias | 517-536 | Polar residues | ||||
Sequence: QGEGDRGNTTGSDNTDTEGS |
Keywords
- Technical term
Sequence databases
Nucleotide Sequence | Protein Sequence | Molecule Type | Status | |
---|---|---|---|---|
AL732541 EMBL· GenBank· DDBJ | - | Genomic DNA | No translation available. | |
BC151023 EMBL· GenBank· DDBJ | AAI51024.1 EMBL· GenBank· DDBJ | mRNA |