| Structural highlights
Disease
[CARD9_HUMAN] Chronic mucocutaneous candidosis;Deep dermatophytosis. The disease is caused by mutations 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. Neutrophils show a selective Candida albicans killing defect with abnormal ultrastructural phagolysosomes and outgrowth of hyphae (PubMed:23335372).[1]
Function
[CARD9_HUMAN] Adapter protein that plays a key role in innate immune response to a number of intracellular pathogens, such as C.albicans and L.monocytogenes. Is at the crossroads of ITAM-tyrosine kinase and the Toll-like receptors (TLR) and NOD2 signaling pathways. Probably controls various innate immune response pathways depending on the intracellular pathogen. In response to L.monocytogenes infection, acts by connecting NOD2 recognition of peptidoglycan to downstream activation of MAP kinases (MAPK) without activating NF-kappa-B. 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). Controls CLEC7A (dectin-1)-mediated myeloid cell activation induced by the yeast cell wall component zymosan, leading to cytokine production and innate anti-fungal immunity: acts by regulating BCL10-MALT1-mediated NF-kappa-B activation pathway. Activates NF-kappa-B via BCL10. In response to the hyphal form of C.albicans, mediates CLEC6A (dectin-2)-induced I-kappa-B kinase ubiquitination, leading to NF-kappa-B activation via interaction with BCL10. In response to fungal infection, may be required for the development and subsequent differentiation of interleukin 17-producing T helper (TH-17) cells.[2]
Publication Abstract from PubMed
CARD9 and CARD11 drive immune cell activation by nucleating Bcl10 polymerization, but are held in an autoinhibited state prior to stimulation. Here, we elucidate the structural basis for this autoinhibition by determining the structure of a region of CARD9 that includes an extensive interface between its caspase recruitment domain (CARD) and coiled-coil domain. We demonstrate, for both CARD9 and CARD11, that disruption of this interface leads to hyperactivation in cells and to the formation of Bcl10-templating filaments in vitro, illuminating the mechanism of action of numerous oncogenic mutations of CARD11. These structural insights enable us to characterize two similar, yet distinct, mechanisms by which autoinhibition is relieved in the course of canonical CARD9 or CARD11 activation. We also dissect the molecular determinants of helical template assembly by solving the structure of the CARD9 filament. Taken together, these findings delineate the structural mechanisms of inhibition and activation within this protein family.
Structures of autoinhibited and polymerized forms of CARD9 reveal mechanisms of CARD9 and CARD11 activation.,Holliday MJ, Witt A, Rodriguez Gama A, Walters BT, Arthur CP, Halfmann R, Rohou A, Dueber EC, Fairbrother WJ Nat Commun. 2019 Jul 11;10(1):3070. doi: 10.1038/s41467-019-10953-z. PMID:31296852[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Drewniak A, Gazendam RP, Tool AT, van Houdt M, Jansen MH, van Hamme JL, van Leeuwen EM, Roos D, Scalais E, de Beaufort C, Janssen H, van den Berg TK, Kuijpers TW. Invasive fungal infection and impaired neutrophil killing in human CARD9 deficiency. Blood. 2013 Mar 28;121(13):2385-92. doi: 10.1182/blood-2012-08-450551. Epub 2013 , Jan 18. PMID:23335372 doi:http://dx.doi.org/10.1182/blood-2012-08-450551
- ↑ Bertin J, Guo Y, Wang L, Srinivasula SM, Jacobson MD, Poyet JL, Merriam S, Du MQ, Dyer MJ, Robison KE, DiStefano PS, Alnemri ES. CARD9 is a novel caspase recruitment domain-containing protein that interacts with BCL10/CLAP and activates NF-kappa B. J Biol Chem. 2000 Dec 29;275(52):41082-6. PMID:11053425 doi:http://dx.doi.org/10.1074/jbc.C000726200
- ↑ Holliday MJ, Witt A, Rodriguez Gama A, Walters BT, Arthur CP, Halfmann R, Rohou A, Dueber EC, Fairbrother WJ. Structures of autoinhibited and polymerized forms of CARD9 reveal mechanisms of CARD9 and CARD11 activation. Nat Commun. 2019 Jul 11;10(1):3070. doi: 10.1038/s41467-019-10953-z. PMID:31296852 doi:http://dx.doi.org/10.1038/s41467-019-10953-z
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