CARD9 Gene

CARD9 (CARD9 stands for "Caspase Recruitment Domain Family Member 9") is a protein-coding gene located on chromosome 9q34.3. Several alternatively spliced transcript variants have been observed, but their full-length nature is not clearly defined.

The protein encoded by this gene is a member of the CARD protein family, which is defined by the presence of a characteristic caspase-associated recruitment domain (CARD). CARD is a protein interaction domain known to be involved in the activation or repression of CARD-containing caspase family members and thus plays an important regulatory role in cell apoptosis. This protein was identified by its selective association with the CARD domain of BCL10, a positive regulator of apoptosis and NF-kappaB activation. It is thought to act as a molecular scaffold for the assembly of a BCL10 signaling complex that activates NF-kappaB.

Diseases associated with CARD9 include:

• Candidiasis, familial, 2

The encoded CARD 9 protein is an adaptor protein that plays a key role in the innate immune response against fungi by forming signaling complexes downstream of C-type lectin receptors. CARD9-mediated signaling is essential for antifungal immunity. It transduces signals in myeloid cells downstream of the C-type lectin receptors CLEC7A (Dectin-1), CLEC6A (Dectin-2), and CLEC4E (Mincle) that recognize pathogen-associated molecular pattern metabolites (PAMPs), such as fungal carbohydrates, and trigger activation of CARD9. After activation, oligomerization occurs. This complex recruits BCL10 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), which stimulate expression of genes encoding proinflammatory cytokines and chemokines.

CARD9 signaling in antigen-presenting cells links innate recognition of fungal antigens to activation of adaptive immunity and provides a cytokine milieu that induces the development of interleukin-17-producing T helper cells (Th17). CARD9 is also involved in myeloid cell activation via classical ITAM-associated receptors. CARD9 is also found in neutrophils and has been shown to be a critical mediator of intercellular communication (Sheng R et al.2021). CARD9 can also be activated independently of BCL10: in this, it forms a complex with RASGRF1 downstream of C-type lectin receptors that recruits and activates HRAS, leading to ERK activation and cytokine production. Acts as an important regulator of the component of the gut microbiota composed of commensal fungi (mycobiota). CARD9 plays an essential role in antifungal immunity against the dissemination of intestinal fungi: it promotes the induction of antifungal IgG antibodies in CX3CR1(+) macrophages to provide protection against the dissemination of C. albicans or C. auris. Also mediates immunity to other pathogens such as certain bacteria, viruses, and parasites; however, CARD9 signaling is redundant to other innate immune responses .

1. Drewniak A et al (2013) Invasive fungal infection and impaired neutrophil killing in human CARD9 deficiency. Blood 121:2385-2392.
2. Drummond RA et al (2015) CARD9-dependent neutrophil recruitment protects against fungal invasion of the central nervous system. Plos Pathogens. doi: 10.1371/journal.ppat.1005293. -
3. Herbst M et al. (2015) Chronic Candida albicans meningitis in a 4-year-old girl with a homozygous mutation in the CARD9 gene (Q295X) Pediatric Infectious Disease Journal 34:999-1002.
4. Sheng R et al.(2021) The Role of CARD9 Deficiency in Neutrophils. Mediators Inflamm 4:6643603.
5. Zhong X et al. (2018) Molecular and physiological roles of the adaptor protein CARD9 in immunity. Cell Death and Disease 9: 52.