Details of Drug Off-Target (DOT)

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

• DOT Name: Caspase recruitment domain-containing protein 8 (CARD8)
• Synonyms: EC 3.4.-.-; CARD-inhibitor of NF-kappa-B-activating ligand; CARDINAL; Tumor up-regulated CARD-containing antagonist of CASP9; TUCAN
• Gene Name: CARD8
• Related Disease:
  Aphthous stomatitis
  Arthritis
  Hereditary periodic fever syndrome
  High blood pressure
  Abdominal aortic aneurysm
  Acute lymphocytic leukaemia
  Acute myelogenous leukaemia
  Advanced cancer
  Alzheimer disease
  Arteriosclerosis
  Atherosclerosis
  Breast cancer
  Breast carcinoma
  Cardiovascular disease
  Cervical cancer
  Cervical carcinoma
  Childhood acute lymphoblastic leukemia
  Colon cancer
  Colon carcinoma
  Crohn disease
  Cryopyrin-associated periodic syndrome
  Essential hypertension
  Extrapulmonary tuberculosis
  Hepatitis C virus infection
  Hepatocellular carcinoma
  Inflammatory bowel disease
  Juvenile idiopathic arthritis
  Listeriosis
  Liver cancer
  Myocardial infarction
  Neoplasm
  Pulmonary tuberculosis
  Tuberculosis
  Ulcerative colitis
  Plasma cell myeloma
  Colorectal carcinoma
  Fetal growth restriction
  Gout
  Inflammatory bowel disease 30
  Melanocytic nevus
  Non-insulin dependent diabetes
  Pleural disease
  Type-1 diabetes
  Type-1/2 diabetes
• UniProt ID: CARD8_HUMAN
• PDB ID: 4IKM; 6K9F; 6XKJ; 7JKQ; 7JN7
• EC Number: 3.4.-.-
• Pfam ID: PF00619 ; PF13553
• Sequence:
  MEKKECPEKSSSSEEELPRRDSGSSRNIDASKLIRLQGSRKLLVDNSIRELQYTKTGIFF
  QAEACVTNDTVYRELPCVSETLCDISHFFQEDDETEAEPLLFRAVPECQLSGGDIPSVSE
  EQESSEGQDSGDICSEENQIVSSYASKVCFEIEEDYKNRQFLGPEGNVDVELIDKSTNRY
  SVWFPTAGWYLWSATGLGFLVRDEVTVTIAFGSWSQHLALDLQHHEQWLVGGPLFDVTAE
  PEEAVAEIHLPHFISLQAGEVDVSWFLVAHFKNEGMVLEHPARVEPFYAVLESPSFSLMG
  ILLRIASGTRLSIPITSNTLIYYHPHPEDIKFHLYLVPSDALLTKAIDDEEDRFHGVRLQ
  TSPPMEPLNFGSSYIVSNSANLKVMPKELKLSYRSPGEIQHFSKFYAGQMKEPIQLEITE
  KRHGTLVWDTEVKPVDLQLVAASAPPPFSGAAFVKENHRQLQARMGDLKGVLDDLQDNEV
  LTENEKELVEQEKTRQSKNEALLSMVEKKGDLALDVLFRSISERDPYLVSYLRQQNL
• Function: Inflammasome sensor, which mediates inflammasome activation in response to various pathogen-associated signals, leading to subsequent pyroptosis of CD4(+) T-cells and macrophages. Inflammasomes are supramolecular complexes that assemble in the cytosol in response to pathogens and other damage-associated signals and play critical roles in innate immunity and inflammation. Acts as a recognition receptor (PRR): recognizes specific pathogens and other damage-associated signals, such as HIV-1 protease activity or Val-boroPro inhibitor, and mediates CARD8 inflammasome activation. In response to pathogen-associated signals, the N-terminal part of CARD8 is degraded by the proteasome, releasing the cleaved C-terminal part of the protein (Caspase recruitment domain-containing protein 8, C-terminus), which polymerizes to initiate the formation of the inflammasome complex: the CARD8 inflammasome directly recruits pro-caspase-1 (proCASP1) independently of PYCARD/ASC and promotes caspase-1 (CASP1) activation, which subsequently cleaves and activates inflammatory cytokines IL1B and IL18 and gasdermin-D (GSDMD), leading to pyroptosis. Ability to sense HIV-1 protease activity leads to the clearance of latent HIV-1 in patient CD4(+) T-cells after viral reactivation; in contrast, HIV-1 can evade CARD8-sensing when its protease remains inactive in infected cells prior to viral budding. Also acts as a negative regulator of the NLRP3 inflammasome. May also act as an inhibitor of NF-kappa-B activation ; [Caspase recruitment domain-containing protein 8]: Constitutes the precursor of the CARD8 inflammasome, which mediates autoproteolytic processing within the FIIND domain to generate the N-terminal and C-terminal parts, which are associated non-covalently in absence of pathogens and other damage-associated signals; [Caspase recruitment domain-containing protein 8, N-terminus]: Regulatory part that prevents formation of the CARD8 inflammasome: in absence of pathogens and other damage-associated signals, interacts with the C-terminal part of CARD8 (Caspase recruitment domain-containing protein 8, C-terminus), preventing activation of the CARD8 inflammasome. In response to pathogen-associated signals, this part is ubiquitinated by the N-end rule pathway and degraded by the proteasome, releasing the cleaved C-terminal part of the protein, which polymerizes and forms the CARD8 inflammasome (Probable) ; [Caspase recruitment domain-containing protein 8, C-terminus]: Constitutes the active part of the CARD8 inflammasome. In absence of pathogens and other damage-associated signals, interacts with the N-terminal part of CARD8 (Caspase recruitment domain-containing protein 8, N-terminus), preventing activation of the CARD8 inflammasome. In response to pathogen-associated signals, the N-terminal part of CARD8 is degraded by the proteasome, releasing this form, which polymerizes to form the CARD8 inflammasome complex: the CARD8 inflammasome complex then directly recruits pro-caspase-1 (proCASP1) and promotes caspase-1 (CASP1) activation, leading to gasdermin-D (GSDMD) cleavage and subsequent pyroptosis.
• Tissue Specificity: High expression in lung, ovary, testis and placenta . Lower expression in heart, kidney and liver . Also expressed in spleen, lymph node and bone marrow .
• KEGG Pathway: NOD-like receptor sig.ling pathway (hsa04621)
• Reactome Pathway:
  Regulation of the apoptosome activity (R-HSA-9627069)
  Formation of apoptosome (R-HSA-111458)

Molecular Interaction Atlas (MIA) of This DOT

44 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Aphthous stomatitis	DISR2T25	Definitive	Biomarker	[1]
Arthritis	DIST1YEL	Definitive	Genetic Variation	[2]
Hereditary periodic fever syndrome	DISS9RWQ	Definitive	Genetic Variation	[2]
High blood pressure	DISY2OHH	Definitive	Genetic Variation	[2]
Abdominal aortic aneurysm	DISD06OF	Strong	Genetic Variation	[3]
Acute lymphocytic leukaemia	DISPX75S	Strong	Genetic Variation	[4]
Acute myelogenous leukaemia	DISCSPTN	Strong	Altered Expression	[5]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[6]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[7]
Arteriosclerosis	DISK5QGC	Strong	Altered Expression	[8]
Atherosclerosis	DISMN9J3	Strong	Altered Expression	[8]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[9]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[9]
Cardiovascular disease	DIS2IQDX	Strong	Genetic Variation	[10]
Cervical cancer	DISFSHPF	Strong	Genetic Variation	[11]
Cervical carcinoma	DIST4S00	Strong	Genetic Variation	[11]
Childhood acute lymphoblastic leukemia	DISJ5D6U	Strong	Genetic Variation	[4]
Colon cancer	DISVC52G	Strong	Altered Expression	[6]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[6]
Crohn disease	DIS2C5Q8	Strong	Genetic Variation	[12]
Cryopyrin-associated periodic syndrome	DISPXXOZ	Strong	Biomarker	[13]
Essential hypertension	DIS7WI98	Strong	Biomarker	[14]
Extrapulmonary tuberculosis	DIS6KM28	Strong	Genetic Variation	[15]
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[16]
Hepatocellular carcinoma	DIS0J828	Strong	Genetic Variation	[11]
Inflammatory bowel disease	DISGN23E	Strong	Biomarker	[17]
Juvenile idiopathic arthritis	DISQZGBV	Strong	Genetic Variation	[18]
Listeriosis	DISKMQBM	Strong	Biomarker	[19]
Liver cancer	DISDE4BI	Strong	Biomarker	[11]
Myocardial infarction	DIS655KI	Strong	Altered Expression	[8]
Neoplasm	DISZKGEW	Strong	Altered Expression	[6]
Pulmonary tuberculosis	DIS6FLUM	Strong	Genetic Variation	[15]
Tuberculosis	DIS2YIMD	Strong	Genetic Variation	[15]
Ulcerative colitis	DIS8K27O	Strong	Genetic Variation	[20]
Plasma cell myeloma	DIS0DFZ0	moderate	Genetic Variation	[21]
Colorectal carcinoma	DIS5PYL0	Limited	Biomarker	[22]
Fetal growth restriction	DIS5WEJ5	Limited	Biomarker	[23]
Gout	DISHC0U7	Limited	Biomarker	[24]
Inflammatory bowel disease 30	DISXOJYY	Limited	Unknown	[12]
Melanocytic nevus	DISYS32D	Limited	Altered Expression	[25]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Genetic Variation	[26]
Pleural disease	DISHT9AE	Limited	Biomarker	[27]
Type-1 diabetes	DIS7HLUB	Limited	Biomarker	[17]
Type-1/2 diabetes	DISIUHAP	Limited	Biomarker	[28]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Caspase recruitment domain-containing protein 8 (CARD8).	[29]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Caspase recruitment domain-containing protein 8 (CARD8).	[30]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Caspase recruitment domain-containing protein 8 (CARD8).	[31]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Caspase recruitment domain-containing protein 8 (CARD8).	[32]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Caspase recruitment domain-containing protein 8 (CARD8).	[33]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Caspase recruitment domain-containing protein 8 (CARD8).	[34]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Caspase recruitment domain-containing protein 8 (CARD8).	[35]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of Caspase recruitment domain-containing protein 8 (CARD8).	[36]
Menthol	DMG2KW7	Approved	Menthol increases the expression of Caspase recruitment domain-containing protein 8 (CARD8).	[37]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Caspase recruitment domain-containing protein 8 (CARD8).	[39]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Caspase recruitment domain-containing protein 8 (CARD8).	[40]
Paraquat	DMR8O3X	Investigative	Paraquat decreases the expression of Caspase recruitment domain-containing protein 8 (CARD8).	[41]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Caspase recruitment domain-containing protein 8 (CARD8).	[38]

References

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• [33] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [34] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
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• [41] Identification of genes associated with paraquat-induced toxicity in SH-SY5Y cells by PCR array focused on apoptotic pathways. J Toxicol Environ Health A. 2008;71(22):1457-67. doi: 10.1080/15287390802329364.