Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTEREN4W)

• DOT Name: NACHT, LRR and PYD domains-containing protein 6 (NLRP6)
• Synonyms: Angiotensin II/vasopressin receptor; PYRIN-containing APAF1-like protein 5
• Gene Name: NLRP6
• Related Disease:
  Colitis
  Advanced cancer
  Aortic valve stenosis
  Atrial fibrillation
  Bacterial endocarditis
  Breast carcinoma
  Cardiac failure
  Colon cancer
  Colon carcinoma
  Congestive heart failure
  Delirium
  Depression
  Disorder of sexual differentiation
  Essential hypertension
  Gastric cancer
  High blood pressure
  Infective endocarditis
  Inflammatory bowel disease
  Keratoconjunctivitis sicca
  Lung cancer
  Lung carcinoma
  Neoplasm
  Nephritis
  Obesity
  Rheumatoid arthritis
  Stomach cancer
  Thyroid gland papillary carcinoma
  Type-1/2 diabetes
  Osteoarthritis
  Gram-positive bacterial infection
  Pneumonia
  Cardiomyopathy
  Graft-versus-host disease
  Hirschsprung disease
  Irritable bowel syndrome
  Non-insulin dependent diabetes
  Periodontitis
• UniProt ID: NLRP6_HUMAN
• PDB ID: 6NCV; 6NDJ
• Pfam ID: PF05729 ; PF17776 ; PF17779 ; PF02758
• Sequence:
  MDQPEAPCSSTGPRLAVARELLLAALEELSQEQLKRFRHKLRDVGPDGRSIPWGRLERAD
  AVDLAEQLAQFYGPEPALEVARKTLKRADARDVAAQLQERRLQRLGLGSGTLLSVSEYKK
  KYREHVLQLHARVKERNARSVKITKRFTKLLIAPESAAPEEAMGPAEEPEPGRARRSDTH
  TFNRLFRRDEEGRRPLTVVLQGPAGIGKTMAAKKILYDWAAGKLYQGQVDFAFFMPCGEL
  LERPGTRSLADLILDQCPDRGAPVPQMLAQPQRLLFILDGADELPALGGPEAAPCTDPFE
  AASGARVLGGLLSKALLPTALLLVTTRAAAPGRLQGRLCSPQCAEVRGFSDKDKKKYFYK
  YFRDERRAERAYRFVKENETLFALCFVPFVCWIVCTVLRQQLELGRDLSRTSKTTTSVYL
  LFITSVLSSAPVADGPRLQGDLRNLCRLAREGVLGRRAQFAEKELEQLELRGSKVQTLFL
  SKKELPGVLETEVTYQFIDQSFQEFLAALSYLLEDGGVPRTAAGGVGTLLRGDAQPHSHL
  VLTTRFLFGLLSAERMRDIERHFGCMVSERVKQEALRWVQGQGQGCPGVAPEVTEGAKGL
  EDTEEPEEEEEGEEPNYPLELLYCLYETQEDAFVRQALCRFPELALQRVRFCRMDVAVLS
  YCVRCCPAGQALRLISCRLVAAQEKKKKSLGKRLQASLGGGSSSQGTTKQLPASLLHPLF
  QAMTDPLCHLSSLTLSHCKLPDAVCRDLSEALRAAPALTELGLLHNRLSEAGLRMLSEGL
  AWPQCRVQTVRVQLPDPQRGLQYLVGMLRQSPALTTLDLSGCQLPAPMVTYLCAVLQHQG
  CGLQTLSLASVELSEQSLQELQAVKRAKPDLVITHPALDGHPQPPKELISTF
• Function: Acts as the sensor component of the NLRP6 inflammasome, which mediates inflammasome activation in response to various pathogen-associated signals, leading to maturation and secretion of IL1B and IL18. 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 and binds specific pathogens and other damage-associated signals, such as lipoteichoic acid (LTA), a cell-wall component of Gram-positive bacteria, or double stranded RNA (dsRNA). May also recognize and bind lipopolysaccharide (LPS), a major component of the outer membrane of Gram-negative bacteria; however, LPS is probably not a major activator of the NLRP6 inflammasome. Following LTA- or dsRNA-binding, NLRP6 undergoes liquid-liquid phase separation (LLPS), enhancing multivalent interactions, an essential step for the formation of the NLRP6 inflammasome polymeric complex. The NLRP6 inflammasome acts by promoting recruitment of effector pro-inflammatory caspases (CASP1 and/or CASP4) that catalyze maturation and secretion of IL1B and IL18 in the extracellular milieu. The NLRP6 inflammasome plays a central role in the maintenance of epithelial integrity and host defense against microbial infections in the intestine. Required to restrict infection against Gram-positive bacteria by recognizing lipoteichoic acid (LTA), leading to recruitment of CASP4 and CASP1, and subsequent maturation and secretion of IL1B and IL18. Involved in intestinal antiviral innate immunity together with DHX15: recognizes and binds viral dsRNA to restrict infection by enteric viruses through the interferon pathway and GSDMD-dependent release of IL18. Required to prevent infection by the apicomplexan parasite Cryptosporidium in enterocytes by promoting GSDMD-dependent release of IL18. The NLRP6 inflammasome may also regulate the gut microbiota composition by acting as a sensor of microbiota-associated metabolites to form a PYCARD/ASC-dependent inflammasome for downstream IL18 release and secretion of antimicrobial peptides. Essential for gut mucosal self-renewal and proliferation. Regulate mucus secretion in an inflammasome- and autophagy-dependent manner to prevent invasion by enteric bacteria,. During systemic bacterial infections, the NLRP6 inflammasome negatively regulates neutrophil recruitment and neutrophil extracellular traps (NETs) formation. May promote peripheral nerve recovery following injury via an inflammasome-independent mechanism.
• Tissue Specificity: Expressed in peripheral blood leukocytes, predominantly in granulocytes and, at lower levels, in CD4(+) and CD8(+) T-cells . Expressed in colonic myofibroblasts (at protein level) .
• KEGG Pathway: NOD-like receptor sig.ling pathway (hsa04621)

Molecular Interaction Atlas (MIA) of This DOT

37 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Colitis	DISAF7DD	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Aortic valve stenosis	DISW7AQ9	Strong	Genetic Variation	[3]
Atrial fibrillation	DIS15W6U	Strong	Genetic Variation	[4]
Bacterial endocarditis	DIS920N0	Strong	Biomarker	[5]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[6]
Cardiac failure	DISDC067	Strong	Biomarker	[7]
Colon cancer	DISVC52G	Strong	Biomarker	[8]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[8]
Congestive heart failure	DIS32MEA	Strong	Biomarker	[7]
Delirium	DIS2OKP1	Strong	Biomarker	[9]
Depression	DIS3XJ69	Strong	Genetic Variation	[10]
Disorder of sexual differentiation	DISRMAEZ	Strong	Altered Expression	[11]
Essential hypertension	DIS7WI98	Strong	Genetic Variation	[12]
Gastric cancer	DISXGOUK	Strong	Altered Expression	[13]
High blood pressure	DISY2OHH	Strong	Genetic Variation	[12]
Infective endocarditis	DIS88NSA	Strong	Biomarker	[5]
Inflammatory bowel disease	DISGN23E	Strong	Biomarker	[14]
Keratoconjunctivitis sicca	DISNOENH	Strong	Biomarker	[15]
Lung cancer	DISCM4YA	Strong	Biomarker	[16]
Lung carcinoma	DISTR26C	Strong	Biomarker	[16]
Neoplasm	DISZKGEW	Strong	Biomarker	[17]
Nephritis	DISQZQ70	Strong	Biomarker	[18]
Obesity	DIS47Y1K	Strong	Biomarker	[19]
Rheumatoid arthritis	DISTSB4J	Strong	Biomarker	[20]
Stomach cancer	DISKIJSX	Strong	Altered Expression	[13]
Thyroid gland papillary carcinoma	DIS48YMM	Strong	Genetic Variation	[21]
Type-1/2 diabetes	DISIUHAP	Strong	Genetic Variation	[10]
Osteoarthritis	DIS05URM	moderate	Altered Expression	[20]
Gram-positive bacterial infection	DISZ44JH	Disputed	Biomarker	[22]
Pneumonia	DIS8EF3M	Disputed	Biomarker	[22]
Cardiomyopathy	DISUPZRG	Limited	Biomarker	[23]
Graft-versus-host disease	DIS0QADF	Limited	Biomarker	[1]
Hirschsprung disease	DISUUSM1	Limited	Altered Expression	[24]
Irritable bowel syndrome	DIS27206	Limited	Biomarker	[25]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Biomarker	[26]
Periodontitis	DISI9JOI	Limited	Altered Expression	[27]

1 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 NACHT, LRR and PYD domains-containing protein 6 (NLRP6).	[28]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of NACHT, LRR and PYD domains-containing protein 6 (NLRP6).	[29]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of NACHT, LRR and PYD domains-containing protein 6 (NLRP6).	[30]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of NACHT, LRR and PYD domains-containing protein 6 (NLRP6).	[31]

References

• [1] Host NLRP6 exacerbates graft-versus-host disease independent of gut microbial composition.Nat Microbiol. 2019 May;4(5):800-812. doi: 10.1038/s41564-019-0373-1. Epub 2019 Mar 11.
• [2] Transcatheter aortic valve replacement for oncology patients with severe symptomatic aortic stenosis: New hope for a complicated medical condition.Catheter Cardiovasc Interv. 2019 Sep 1;94(3):446-447. doi: 10.1002/ccd.28484.
• [3] Aortic annulus measurement with computed tomography angiography reduces aortic regurgitation after transfemoral aortic valve replacement compared to 3-D echocardiography: a single-centre experience.Clin Res Cardiol. 2019 Nov;108(11):1266-1275. doi: 10.1007/s00392-019-01462-6. Epub 2019 Apr 10.
• [4] Management of aortic valve replacement according to the gradient across symptomatic aortic valve stenosis and its prognostic impact.Echocardiography. 2019 Dec;36(12):2136-2144. doi: 10.1111/echo.14531. Epub 2019 Nov 8.
• [5] Incidence and factors associated with infective endocarditis in patients undergoing left-sided heart valve replacement.Eur Heart J. 2018 Jul 21;39(28):2668-2675. doi: 10.1093/eurheartj/ehy153.
• [6] Dihydropyrimidine dehydrogenase activity and messenger RNA level may be related to the antitumor effect of 5-fluorouracil on human tumor xenografts in nude mice.Clin Cancer Res. 1999 Apr;5(4):883-9.
• [7] High- Versus Low-Gradient Severe Aortic Stenosis: Demographics, Clinical Outcomes, and Effects of the Initial Aortic Valve Replacement Strategy on Long-Term Prognosis.Circ Cardiovasc Interv. 2017 May;10(5):e004796. doi: 10.1161/CIRCINTERVENTIONS.116.004796.
• [8] NLRP6 function in inflammatory monocytes reduces susceptibility to chemically induced intestinal injury.Mucosal Immunol. 2017 Mar;10(2):434-445. doi: 10.1038/mi.2016.55. Epub 2016 Jun 29.
• [9] Incremental cost and length of stay associated with postprocedure delirium in transcatheter and surgical aortic valve replacement patients in the United States.Catheter Cardiovasc Interv. 2019 May 1;93(6):1132-1136. doi: 10.1002/ccd.28014. Epub 2018 Dec 14.
• [10] The association between electrocardiographic R wave peak time and coronary artery disease severity in patients with non-ST segment elevation myocardial infarction and unstable angina pectoris.J Electrocardiol. 2018 Mar-Apr;51(2):230-235. doi: 10.1016/j.jelectrocard.2017.09.009. Epub 2017 Sep 27.
• [11] Effect of mild moxibustion on intestinal microbiota and NLRP6 inflammasome signaling in rats with post-inflammatory irritable bowel syndrome.World J Gastroenterol. 2019 Aug 28;25(32):4696-4714. doi: 10.3748/wjg.v25.i32.4696.
• [12] Sex-specific effects of NLRP6/AVR and ADM loci on susceptibility to essential hypertension in a Sardinian population.PLoS One. 2013 Oct 11;8(10):e77562. doi: 10.1371/journal.pone.0077562. eCollection 2013.
• [13] Long noncoding RNA OIP5-AS1 aggravates cell proliferation, migration in gastric cancer by epigenetically silencing NLRP6 expression via binding EZH2.J Cell Biochem. 2020 Jan;121(1):353-362. doi: 10.1002/jcb.29183. Epub 2019 Jun 20.
• [14] NLRP6 Protects Il10(-/-) Mice from Colitis by Limiting Colonization of Akkermansia muciniphila.Cell Rep. 2017 Apr 25;19(4):733-745. doi: 10.1016/j.celrep.2017.03.080.
• [15] TLR4-MyD88 pathway promotes the imbalanced activation of NLRP3/NLRP6 via caspase-8 stimulation after alkali burn injury.Exp Eye Res. 2018 Nov;176:59-68. doi: 10.1016/j.exer.2018.07.001. Epub 2018 Jul 2.
• [16] Is NLRP3 or NLRP6 inflammasome activation associated with inflammation-related lung tumorigenesis induced by benzo(a)pyrene and lipopolysaccharide?.Ecotoxicol Environ Saf. 2019 Dec 15;185:109687. doi: 10.1016/j.ecoenv.2019.109687. Epub 2019 Sep 24.
• [17] NLRP6, decreased in gastric cancer, suppresses tumorigenicity of gastric cancer cells.Cancer Manag Res. 2018 Nov 27;10:6431-6444. doi: 10.2147/CMAR.S182980. eCollection 2018.
• [18] Loss of NLRP6 expression increases the severity of acute kidney injury.Nephrol Dial Transplant. 2020 Apr 1;35(4):587-598. doi: 10.1093/ndt/gfz169.
• [19] Outcomes of aortic valve replacement via partial upper sternotomy versus conventional aortic valve replacement in obese patients.Interact Cardiovasc Thorac Surg. 2018 Oct 1;27(4):481-486. doi: 10.1093/icvts/ivy083.
• [20] NLRP6 facilitates the interaction between TAB2/3 and TRIM38 in rheumatoid arthritis fibroblast-like synoviocytes.FEBS Lett. 2017 Apr;591(8):1141-1149. doi: 10.1002/1873-3468.12622. Epub 2017 Mar 30.
• [21] Targeted next-generation sequencing in papillary thyroid carcinoma patients looking for germline variants predisposing to the disease.Endocrine. 2019 Jun;64(3):622-631. doi: 10.1007/s12020-019-01878-0. Epub 2019 Mar 2.
• [22] NLRP6 negatively regulates pulmonary host defense in Gram-positive bacterial infection through modulating neutrophil recruitment and function.PLoS Pathog. 2018 Sep 24;14(9):e1007308. doi: 10.1371/journal.ppat.1007308. eCollection 2018 Sep.
• [23] Arterial Properties as Determinants of Left Ventricular Mass and Fibrosis in Severe Aortic Stenosis: Findings From ACRIN PA 4008.J Am Heart Assoc. 2019 Jan 8;8(1):e03742. doi: 10.1161/JAHA.118.010271.
• [24] Reduced expression of the NLRP6 inflammasome in the colon of patients with Hirschsprung's disease.J Pediatr Surg. 2019 Aug;54(8):1573-1577. doi: 10.1016/j.jpedsurg.2018.08.059. Epub 2018 Sep 7.
• [25] Corticotropin-releasing factor induces inflammatory cytokines via the NLRP6-inflammatory cytokine axis in a murine model of irritable bowel syndrome.J Dig Dis. 2019 Mar;20(3):143-151. doi: 10.1111/1751-2980.12704. Epub 2019 Mar 5.
• [26] Specific inflammasomes in complex diseases.Clin Immunol. 2013 Jun;147(3):223-8. doi: 10.1016/j.clim.2012.12.006. Epub 2012 Dec 21.
• [27] NLRP6 Induces Pyroptosis by Activation of Caspase-1 in Gingival Fibroblasts.J Dent Res. 2018 Nov;97(12):1391-1398. doi: 10.1177/0022034518775036. Epub 2018 May 23.
• [28] 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.
• [29] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [30] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [31] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.