Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJ81AWD)

• DOT Name: Caspase recruitment domain-containing protein 9 (CARD9)
• Synonyms: hCARD9
• Gene Name: CARD9
• Related Disease:
  Arteriosclerosis
  Atherosclerosis
  Autoimmune disease
  B-cell neoplasm
  Candidemia
  Candidiasis
  Candidiasis, invasive
  Chronic mucocutaneous candidiasis
  Colon cancer
  Colon carcinoma
  Crohn disease
  IgA nephropathy
  Inborn error of immunity
  Invasive candidiasis
  Lung cancer
  Lung carcinoma
  Metabolic disorder
  Neoplasm
  Obesity
  Obsolete deep dermatophytosis
  Osteomyelitis
  Predisposition to invasive fungal disease due to CARD9 deficiency
  Skin disease
  Tuberculosis
  Autoimmune disease, susceptibility to, 6
  Autoimmune thyroid disease
  Coeliac disease
  Colorectal carcinoma
  Common variable immunodeficiency
  Juvenile idiopathic arthritis
  Lupus nephritis
  Renal fibrosis
  STAT3-related early-onset multisystem autoimmune disease
  Systemic lupus erythematosus
  Type-1 diabetes
  Colitis
  Advanced cancer
  Ankylosing spondylitis
  Dermatophytosis
  Psoriasis
  Rheumatoid arthritis
  Sclerosing cholangitis
  Squamous cell carcinoma
  Tinea infection
  Ulcerative colitis
• UniProt ID: CARD9_HUMAN
• PDB ID: 6E25; 6E26; 6E27; 6E28; 6N2M; 6N2P
• Pfam ID: PF00619
• Sequence:
  MSDYENDDECWSVLEGFRVTLTSVIDPSRITPYLRQCKVLNPDDEEQVLSDPNLVIRKRK
  VGVLLDILQRTGHKGYVAFLESLELYYPQLYKKVTGKEPARVFSMIIDASGESGLTQLLM
  TEVMKLQKKVQDLTALLSSKDDFIKELRVKDSLLRKHQERVQRLKEECEAGSRELKRCKE
  ENYDLAMRLAHQSEEKGAALMRNRDLQLEIDQLKHSLMKAEDDCKVERKHTLKLRHAMEQ
  RPSQELLWELQQEKALLQARVQELEASVQEGKLDRSSPYIQVLEEDWRQALRDHQEQANT
  IFSLRKDLRQGEARRLRCMEEKEMFELQCLALRKDSKMYKDRIEAILLQMEEVAIERDQA
  IATREELHAQHARGLQEKDALRKQVRELGEKADELQLQVFQCEAQLLAVEGRLRRQQLET
  LVLSSDLEDGSPRRSQELSLPQDLEDTQLSDKGCLAGGGSPKQPFAALHQEQVLRNPHDA
  GLSSGEPPEKERRRLKESFENYRRKRALRKMQKGWRQGEEDRENTTGSDNTDTEGS
• Function: Adapter protein that plays a key role in innate immune response against fungi by forming signaling complexes downstream of C-type lectin receptors. CARD9-mediated signals are essential for antifungal immunity against a subset of fungi from the phylum Ascomycota. 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. 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. 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. 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. 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. Acts as an important regulator of the intestinal commensal fungi (mycobiota) component of the gut microbiota. 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. Also mediates immunity against other pathogens, such as certain bacteria, viruses and parasites; CARD9 signaling is however redundant with other innate immune responses. 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.
• Tissue Specificity: Expression is restricted to several populations of phagocytes, such as macrophages, monocytes, and dendritic cells . Highly expressed in spleen . Also detected in liver, placenta, lung, peripheral blood leukocytes and in brain .
• KEGG Pathway:
  NOD-like receptor sig.ling pathway (hsa04621)
  C-type lectin receptor sig.ling pathway (hsa04625)
  Tuberculosis (hsa05152)
  Herpes simplex virus 1 infection (hsa05168)
• Reactome Pathway:
  CLEC7A (Dectin-1) signaling (R-HSA-5607764)
  NOD1/2 Signaling Pathway (R-HSA-168638)

Molecular Interaction Atlas (MIA) of This DOT

45 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[1]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[1]
Autoimmune disease	DISORMTM	Strong	Biomarker	[2]
B-cell neoplasm	DISVY326	Strong	Altered Expression	[3]
Candidemia	DISVKFN7	Strong	Altered Expression	[4]
Candidiasis	DISIRYMU	Strong	Genetic Variation	[5]
Candidiasis, invasive	DIS5VDG3	Strong	Biomarker	[6]
Chronic mucocutaneous candidiasis	DISPSGYF	Strong	Genetic Variation	[7]
Colon cancer	DISVC52G	Strong	Biomarker	[8]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[8]
Crohn disease	DIS2C5Q8	Strong	Biomarker	[9]
IgA nephropathy	DISZ8MTK	Strong	Genetic Variation	[10]
Inborn error of immunity	DISNGCMN	Strong	Biomarker	[11]
Invasive candidiasis	DIS5EI0L	Strong	Biomarker	[6]
Lung cancer	DISCM4YA	Strong	Biomarker	[8]
Lung carcinoma	DISTR26C	Strong	Biomarker	[8]
Metabolic disorder	DIS71G5H	Strong	Biomarker	[12]
Neoplasm	DISZKGEW	Strong	Biomarker	[8]
Obesity	DIS47Y1K	Strong	Biomarker	[12]
Obsolete deep dermatophytosis	DISV8T5S	Strong	Autosomal recessive	[13]
Osteomyelitis	DIS0VUZL	Strong	Biomarker	[14]
Predisposition to invasive fungal disease due to CARD9 deficiency	DISWAQLO	Strong	Autosomal recessive	[15]
Skin disease	DISDW8R6	Strong	Biomarker	[16]
Tuberculosis	DIS2YIMD	Strong	Biomarker	[17]
Autoimmune disease, susceptibility to, 6	DISHNUXI	moderate	Genetic Variation	[18]
Autoimmune thyroid disease	DISIHC6A	moderate	Genetic Variation	[18]
Coeliac disease	DISIY60C	moderate	Genetic Variation	[18]
Colorectal carcinoma	DIS5PYL0	moderate	Biomarker	[19]
Common variable immunodeficiency	DISHE7JQ	moderate	Genetic Variation	[18]
Juvenile idiopathic arthritis	DISQZGBV	moderate	Genetic Variation	[18]
Lupus nephritis	DISCVGPZ	moderate	Altered Expression	[20]
Renal fibrosis	DISMHI3I	moderate	Altered Expression	[20]
STAT3-related early-onset multisystem autoimmune disease	DISAXTN7	moderate	Genetic Variation	[18]
Systemic lupus erythematosus	DISI1SZ7	moderate	Genetic Variation	[18]
Type-1 diabetes	DIS7HLUB	moderate	Genetic Variation	[18]
Colitis	DISAF7DD	Disputed	Genetic Variation	[21]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[19]
Ankylosing spondylitis	DISRC6IR	Limited	Genetic Variation	[22]
Dermatophytosis	DISM7JPJ	Limited	Genetic Variation	[23]
Psoriasis	DIS59VMN	Limited	Genetic Variation	[22]
Rheumatoid arthritis	DISTSB4J	Limited	Biomarker	[2]
Sclerosing cholangitis	DIS7GZNB	Limited	Genetic Variation	[22]
Squamous cell carcinoma	DISQVIFL	Limited	Altered Expression	[24]
Tinea infection	DISXMEII	Limited	Genetic Variation	[23]
Ulcerative colitis	DIS8K27O	Limited	Genetic Variation	[25]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Caspase recruitment domain-containing protein 9 (CARD9).	[26]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Caspase recruitment domain-containing protein 9 (CARD9).	[34]

8 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Caspase recruitment domain-containing protein 9 (CARD9).	[27]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Caspase recruitment domain-containing protein 9 (CARD9).	[28]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Caspase recruitment domain-containing protein 9 (CARD9).	[29]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Caspase recruitment domain-containing protein 9 (CARD9).	[30]
Menthol	DMG2KW7	Approved	Menthol increases the expression of Caspase recruitment domain-containing protein 9 (CARD9).	[31]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Caspase recruitment domain-containing protein 9 (CARD9).	[32]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Caspase recruitment domain-containing protein 9 (CARD9).	[33]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Caspase recruitment domain-containing protein 9 (CARD9).	[35]

References

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• [2] CARD9 mediates dendritic cell-induced development of Lyn deficiency-associated autoimmune and inflammatory diseases.Sci Signal. 2019 Oct 8;12(602):eaao3829. doi: 10.1126/scisignal.aao3829.
• [3] Zinc rescues obesity-induced cardiac hypertrophy via stimulating metallothionein to suppress oxidative stress-activated BCL10/CARD9/p38 MAPK pathway.J Cell Mol Med. 2017 Jun;21(6):1182-1192. doi: 10.1111/jcmm.13050. Epub 2017 Feb 3.
• [4] Dok3-protein phosphatase 1 interaction attenuates Card9 signaling and neutrophil-dependent antifungal immunity.J Clin Invest. 2019 Jun 10;129(7):2717-2729. doi: 10.1172/JCI126341. eCollection 2019 Jun 10.
• [5] Endogenous Candida endophthalmitis and osteomyelitis associated with CARD9 deficiency.BMJ Case Rep. 2016 Mar 3;2016:bcr2015214117. doi: 10.1136/bcr-2015-214117.
• [6] A 7-Year-Old Child With Headaches and Prolonged Fever Associated With Oral and Nail Lesions.Open Forum Infect Dis. 2019 Nov 3;6(11):ofz229. doi: 10.1093/ofid/ofz229. eCollection 2019 Nov.
• [7] Oral Administration of Human Polyvalent IgG by Mouthwash as an Adjunctive Treatment of Chronic Oral Candidiasis.Front Immunol. 2018 Dec 21;9:2956. doi: 10.3389/fimmu.2018.02956. eCollection 2018.
• [8] CARD9 prevents lung cancer development by suppressing the expansion of myeloid-derived suppressor cells and IDO production.Int J Cancer. 2019 Oct 15;145(8):2225-2237. doi: 10.1002/ijc.32355. Epub 2019 May 6.
• [9] Influence of Crohn's disease related polymorphisms in innate immune function on ileal microbiome.PLoS One. 2019 Feb 28;14(2):e0213108. doi: 10.1371/journal.pone.0213108. eCollection 2019.
• [10] The interaction effect of rs4077515 and rs17019602 increases the susceptibility to IgA nephropathy.Oncotarget. 2017 Aug 23;8(44):76492-76497. doi: 10.18632/oncotarget.20401. eCollection 2017 Sep 29.
• [11] A young girl with severe cerebral fungal infection due to card 9 deficiency.Clin Immunol. 2018 Jun;191:21-26. doi: 10.1016/j.clim.2018.01.002. Epub 2018 Jan 4.
• [12] The essential function of CARD9 in diet-induced inflammation and metabolic disorders in mice.J Cell Mol Med. 2018 Jun;22(6):2993-3004. doi: 10.1111/jcmm.13494. Epub 2018 Mar 25.
• [13] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [14] The nonreceptor tyrosine kinase SYK drives caspase-8/NLRP3 inflammasome-mediated autoinflammatory osteomyelitis.J Biol Chem. 2020 Mar 13;295(11):3394-3400. doi: 10.1074/jbc.RA119.010623. Epub 2019 Nov 12.
• [15] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [16] Cutting Edge: Dysregulated CARD9 Signaling in Neutrophils Drives Inflammation in a Mouse Model of Neutrophilic Dermatoses.J Immunol. 2018 Sep 15;201(6):1639-1644. doi: 10.4049/jimmunol.1800760. Epub 2018 Aug 6.
• [17] Dectin-1-Syk-CARD9 Signaling Pathway in TB Immunity.Front Immunol. 2018 Feb 13;9:225. doi: 10.3389/fimmu.2018.00225. eCollection 2018.
• [18] Meta-analysis of shared genetic architecture across ten pediatric autoimmune diseases.Nat Med. 2015 Sep;21(9):1018-27. doi: 10.1038/nm.3933. Epub 2015 Aug 24.
• [19] The Role of Adaptor Protein CARD9 in Colitis-Associated Cancer.Mol Ther Oncolytics. 2019 Aug 30;15:1-6. doi: 10.1016/j.omto.2019.08.007. eCollection 2019 Dec 20.
• [20] Quantitative expression of C-type lectin receptors in humans and mice.Int J Mol Sci. 2012;13(8):10113-10131. doi: 10.3390/ijms130810113. Epub 2012 Aug 14.
• [21] Malassezia Is Associated with Crohn's Disease and Exacerbates Colitis in Mouse Models.Cell Host Microbe. 2019 Mar 13;25(3):377-388.e6. doi: 10.1016/j.chom.2019.01.007. Epub 2019 Mar 5.
• [22] Analysis of five chronic inflammatory diseases identifies 27 new associations and highlights disease-specific patterns at shared loci.Nat Genet. 2016 May;48(5):510-8. doi: 10.1038/ng.3528. Epub 2016 Mar 14.
• [23] Novel CARD9 mutation in a patient with chronic invasive dermatophyte infection (tinea profunda).J Cutan Pathol. 2020 Feb;47(2):166-170. doi: 10.1111/cup.13574. Epub 2019 Oct 29.
• [24] CARD9 downregulation suppresses the growth of oral squamous cell carcinoma by regulating NF-B.Oral Dis. 2019 Nov;25(8):1886-1896. doi: 10.1111/odi.13157. Epub 2019 Oct 11.
• [25] Genome-wide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease.Nat Genet. 2017 Feb;49(2):256-261. doi: 10.1038/ng.3760. Epub 2017 Jan 9.
• [26] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [27] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [28] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [29] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [30] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [31] Repurposing L-menthol for systems medicine and cancer therapeutics? L-menthol induces apoptosis through caspase 10 and by suppressing HSP90. OMICS. 2016 Jan;20(1):53-64.
• [32] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [33] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [34] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [35] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.