CARD9
entrez
64170
canonical
uniprot
Q9H257
canonical
ensembl
ENSG00000187796
resolver
ensembl
ENSG00000289701
resolver
ensp
ENSP00000360797
resolver
ensp
ENSP00000360799
resolver
genesymbol
CARD9
resolver
hgnc
HGNC:16391
resolver
uniprot
Q5SXM5
resolver
uniprot
Q5SXM6
resolver
uniprot
Q9H854
resolver
uniprot_entry
CARD9_HUMAN
resolver
uniprot_sec
Q5SXM5
resolver
uniprot_sec
Q5SXM6
resolver
uniprot_sec
Q9H854
resolver
activity_regulation
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 (PubMed:31296852). 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:26488816, PubMed:31296852). Zinc-binding inhibits activation by stabilizing the CARD ground-state conformation and restricting its capacity to form BCL10-nucleating filaments (PubMed:30206119). {ECO:0000269|PubMed:26488816, ECO:0000269|PubMed:30206119, ECO:0000269|PubMed:31296852}.
uniprot
proteins
amino_acid_sequence
MSDYENDDECWSVLEGFRVTLTSVIDPSRITPYLRQCKVLNPDDEEQVLSDPNLVIRKRKVGVLLDILQRTGHKGYVAFLESLELYYPQLYKKVTGKEPARVFSMIIDASGESGLTQLLMTEVMKLQKKVQDLTALLSSKDDFIKELRVKDSLLRKHQERVQRLKEECEAGSRELKRCKEENYDLAMRLAHQSEEKGAALMRNRDLQLEIDQLKHSLMKAEDDCKVERKHTLKLRHAMEQRPSQELLWELQQEKALLQARVQELEASVQEGKLDRSSPYIQVLEEDWRQALRDHQEQANTIFSLRKDLRQGEARRLRCMEEKEMFELQCLALRKDSKMYKDRIEAILLQMEEVAIERDQAIATREELHAQHARGLQEKDALRKQVRELGEKADELQLQVFQCEAQLLAVEGRLRRQQLETLVLSSDLEDGSPRRSQELSLPQDLEDTQLSDKGCLAGGGSPKQPFAALHQEQVLRNPHDAGLSSGEPPEKERRRLKESFENYRRKRALRKMQKGWRQGEEDRENTTGSDNTDTEGS
uniprot
proteins
disease_involvement
DISEASE: Immunodeficiency 103, susceptibility to fungal infections (IMD103) [MIM:212050]: An autosomal recessive primary immunodeficiency disorder with altered immune responses and impaired clearance of fungal infections, selective against Candida. It is characterized by persistent and/or recurrent infections of the skin, nails and mucous membranes caused by organisms of the genus Candida, mainly Candida albicans. {ECO:0000269|PubMed:19864672, ECO:0000269|PubMed:23335372, ECO:0000269|PubMed:24131138, ECO:0000269|PubMed:24231284, ECO:0000269|PubMed:24704721, ECO:0000269|PubMed:25057046, ECO:0000269|PubMed:25372963, ECO:0000269|PubMed:25702837, ECO:0000269|PubMed:25933095, ECO:0000269|PubMed:26044242, ECO:0000269|PubMed:26440558, ECO:0000269|PubMed:26521038, ECO:0000269|PubMed:26658378, ECO:0000269|PubMed:26679537, ECO:0000269|PubMed:26941346, ECO:0000269|PubMed:26961233, ECO:0000269|PubMed:27777981, ECO:0000269|PubMed:28391957, ECO:0000269|PubMed:28984994, ECO:0000269|PubMed:29080677, ECO:0000269|PubMed:29307770, ECO:0000269|PubMed:31296852, ECO:0000269|PubMed:31469433, ECO:0000269|PubMed:33548172, ECO:0000269|PubMed:33558980}. Note=The disease is caused by variants affecting the gene represented in this entry. Defects induce reduced numbers of CD4(+) Th17 lymphocytes as well as a lack of monocyte-derived cytokines in response to Candida strains (PubMed:23335372). Neutrophils show a selective Candida albicans killing defect with abnormal ultrastructural phagolysosomes and outgrowth of hyphae (PubMed:23335372). {ECO:0000269|PubMed:23335372}.
uniprot
proteins
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:26961233, PubMed:33558980). CARD9-mediated signals are essential for antifungal immunity against a subset of fungi from the phylum Ascomycota (PubMed:24231284, PubMed:25057046, PubMed:25702837, PubMed:26521038, PubMed:26679537, PubMed:26961233, PubMed:27777981, PubMed:29080677, PubMed:33558980). 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 (By similarity). 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:11053425, PubMed:26488816, PubMed:26961233, PubMed:31296852, PubMed:33558980). 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:24231284). 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 (By similarity). 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 (By similarity). Acts as an important regulator of the intestinal commensal fungi (mycobiota) component of the gut microbiota (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 (By similarity). 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 (By similarity). {ECO:0000250|UniProtKB:A2AIV8, ECO:0000269|PubMed:11053425, ECO:0000269|PubMed:24231284, ECO:0000269|PubMed:25057046, ECO:0000269|PubMed:25702837, ECO:0000269|PubMed:26488816, ECO:0000269|PubMed:26521038, ECO:0000269|PubMed:26679537, ECO:0000269|PubMed:26961233, ECO:0000269|PubMed:27777981, ECO:0000269|PubMed:29080677, ECO:0000269|PubMed:31296852, ECO:0000269|PubMed:33548172, ECO:0000269|PubMed:33558980}.
uniprot
proteins
mass_dalton
62241
uniprot
proteins
mutagenesis
MUTAGEN 10; /note="C->A: Strongly reduced zinc-binding."; /evidence="ECO:0000269|PubMed:30206119"; MUTAGEN 15; /note="E->R: Abolished homooligomerization and formation of BCL10-nucleating filaments."; /evidence="ECO:0000269|PubMed:31296852"; MUTAGEN 35; /note="R->E: Abolished homooligomerization and formation of BCL10-nucleating filaments."; /evidence="ECO:0000269|PubMed:31296852"; MUTAGEN 37; /note="C->A: Does not affect zinc-binbing."; /evidence="ECO:0000269|PubMed:30206119"; MUTAGEN 43; /note="D->R: Abolished homooligomerization and formation of BCL10-nucleating filaments."; /evidence="ECO:0000269|PubMed:31296852"; MUTAGEN 58; /note="K->D: Abolished homooligomerization and formation of BCL10-nucleating filaments."; /evidence="ECO:0000269|PubMed:31296852"; MUTAGEN 66; /note="D->R: Abolished homooligomerization and formation of BCL10-nucleating filaments."; /evidence="ECO:0000269|PubMed:31296852"; MUTAGEN 73; /note="H->A: Strongly reduced zinc-binding."; /evidence="ECO:0000269|PubMed:30206119"; MUTAGEN 101; /note="R->Q: Disruption of the linker region, relieving autoinhibition and leading to activation of NF-kappa-B."; /evidence="ECO:0000269|PubMed:31296852"; MUTAGEN 103; /note="F->L: Disruption of the linker region, relieving autoinhibition and leading to activation of NF-kappa-B."; /evidence="ECO:0000269|PubMed:31296852"; MUTAGEN 107; /note="I->E: Disruption of the linker region, relieving autoinhibition and leading to activation of NF-kappa-B. Constitutively forms BCL10-nucleating filaments."; /evidence="ECO:0000269|PubMed:31296852"; MUTAGEN 111; /note="G->S: Disruption of the linker region, relieving autoinhibition and leading to activation of NF-kappa-B."; /evidence="ECO:0000269|PubMed:31296852"; MUTAGEN 114; /note="G->D: Disruption of the linker region, relieving autoinhibition and leading to activation of NF-kappa-B."; /evidence="ECO:0000269|PubMed:31296852"; MUTAGEN 115; /note="L->I: Disruption of the linker region, relieving autoinhibition and leading to activation of NF-kappa-B. Constitutively forms BCL10-nucleating filaments."; /evidence="ECO:0000269|PubMed:31296852"; MUTAGEN 125; /note="K->R: Reduced cytokine production in response to C.albicans infection. Impaired NF-kappa-B transcriptional activity. Does not affect interaction with BCL10."; /evidence="ECO:0000269|PubMed:26488816
uniprot
proteins
post_translational_modification
PTM: 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 (By similarity). Phosphorylated at Thr-531 and Thr-533 by CK2 following interaction with VHL, leading to inhibit the ability to activate NF-kappa-B (By similarity). {ECO:0000250|UniProtKB:A2AIV8, ECO:0000250|UniProtKB:Q9EPY0}.; PTM: 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 (PubMed:26488816, PubMed:31296852). Deubiquitinated at Lys-125 by USP15, inhibiting CARD9 (PubMed:33093067). {ECO:0000269|PubMed:26488816, ECO:0000269|PubMed:31296852, ECO:0000269|PubMed:33093067}.
uniprot
proteins
pubmed
11053425
uniprot
proteins
pubmed
14702039
uniprot
proteins
pubmed
15164053
uniprot
proteins
pubmed
15489334
uniprot
proteins
pubmed
18088087
uniprot
proteins
pubmed
19864672
uniprot
proteins
pubmed
23186163
uniprot
proteins
pubmed
23335372
uniprot
proteins
pubmed
24131138
uniprot
proteins
pubmed
24231284
uniprot
proteins
pubmed
24704721
uniprot
proteins
pubmed
24960071
uniprot
proteins
pubmed
25057046
uniprot
proteins
pubmed
25372963
uniprot
proteins
pubmed
25702837
uniprot
proteins
pubmed
25933095
uniprot
proteins
pubmed
26044242
uniprot
proteins
pubmed
26440558
uniprot
proteins
pubmed
26488816
uniprot
proteins
pubmed
26521038
uniprot
proteins
pubmed
26658378
uniprot
proteins
pubmed
26679537
uniprot
proteins
pubmed
26941346
uniprot
proteins
pubmed
26961233
uniprot
proteins
pubmed
27777981
uniprot
proteins
pubmed
28391957
uniprot
proteins
pubmed
28984994
uniprot
proteins
pubmed
29080677
uniprot
proteins
pubmed
29307770
uniprot
proteins
pubmed
30206119
uniprot
proteins
pubmed
31296852
uniprot
proteins
pubmed
31469433
uniprot
proteins
pubmed
33093067
uniprot
proteins
pubmed
33548172
uniprot
proteins
pubmed
33558980
uniprot
proteins
sequence_length
536
uniprot
proteins
subcellular_location
SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:11053425, ECO:0000269|PubMed:26488816}.
uniprot
proteins