Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTGR132Z)

• DOT Name: NACHT, LRR and PYD domains-containing protein 12 (NLRP12)
• Synonyms: Monarch-1; PYRIN-containing APAF1-like protein 7; Regulated by nitric oxide
• Gene Name: NLRP12
• Related Disease:
  Malaria
  Relapsing fever
  Adult glioblastoma
  Amyloidosis
  Autoinflammatory syndrome
  Autosomal dominant familial periodic fever
  Cataract
  Clear cell renal carcinoma
  Colitis
  Colon cancer
  Colon carcinoma
  Common variable immunodeficiency
  Coronary atherosclerosis
  Coronary heart disease
  Depression
  Familial cold autoinflammatory syndrome
  Familial cold autoinflammatory syndrome 2
  Familial Mediterranean fever
  Glioblastoma multiforme
  Glioma
  Hepatocellular carcinoma
  Hereditary periodic fever syndrome
  Inflammatory bowel disease
  Muckle-Wells syndrome
  Non-immunoglobulin-mediated membranoproliferative glomerulonephritis
  Obesity
  Papillary renal cell carcinoma
  Periodic fever syndrome
  Pharyngitis
  Pneumonia
  Pneumonitis
  Prostate cancer
  Prostate carcinoma
  Renal cell carcinoma
  Ulcerative colitis
  Corneal disease
  Keratitis
  Alzheimer disease
  Alzheimer disease 3
  Bacterial infection
  Carcinoid syndrome
  Stroke
  Tuberculosis
• UniProt ID: NAL12_HUMAN
• PDB ID: 2L6A; 4XHS; 5H7N
• Pfam ID: PF14484 ; PF13516 ; PF05729 ; PF17776 ; PF17779 ; PF02758
• Sequence:
  MLRTAGRDGLCRLSTYLEELEAVELKKFKLYLGTATELGEGKIPWGSMEKAGPLEMAQLL
  ITHFGPEEAWRLALSTFERINRKDLWERGQREDLVRDTPPGGPSSLGNQSTCLLEVSLVT
  PRKDPQETYRDYVRRKFRLMEDRNARLGECVNLSHRYTRLLLVKEHSNPMQVQQQLLDTG
  RGHARTVGHQASPIKIETLFEPDEERPEPPRTVVMQGAAGIGKSMLAHKVMLDWADGKLF
  QGRFDYLFYINCREMNQSATECSMQDLIFSCWPEPSAPLQELIRVPERLLFIIDGFDELK
  PSFHDPQGPWCLCWEEKRPTELLLNSLIRKKLLPELSLLITTRPTALEKLHRLLEHPRHV
  EILGFSEAERKEYFYKYFHNAEQAGQVFNYVRDNEPLFTMCFVPLVCWVVCTCLQQQLEG
  GGLLRQTSRTTTAVYMLYLLSLMQPKPGAPRLQPPPNQRGLCSLAADGLWNQKILFEEQD
  LRKHGLDGEDVSAFLNMNIFQKDINCERYYSFIHLSFQEFFAAMYYILDEGEGGAGPDQD
  VTRLLTEYAFSERSFLALTSRFLFGLLNEETRSHLEKSLCWKVSPHIKMDLLQWIQSKAQ
  SDGSTLQQGSLEFFSCLYEIQEEEFIQQALSHFQVIVVSNIASKMEHMVSSFCLKRCRSA
  QVLHLYGATYSADGEDRARCSAGAHTLLVQLPERTVLLDAYSEHLAAALCTNPNLIELSL
  YRNALGSRGVKLLCQGLRHPNCKLQNLRLKRCRISSSACEDLSAALIANKNLTRMDLSGN
  GVGFPGMMLLCEGLRHPQCRLQMIQLRKCQLESGACQEMASVLGTNPHLVELDLTGNALE
  DLGLRLLCQGLRHPVCRLRTLWLKICRLTAAACDELASTLSVNQSLRELDLSLNELGDLG
  VLLLCEGLRHPTCKLQTLRLGICRLGSAACEGLSVVLQANHNLRELDLSFNDLGDWGLWL
  LAEGLQHPACRLQKLWLDSCGLTAKACENLYFTLGINQTLTDLYLTNNALGDTGVRLLCK
  RLSHPGCKLRVLWLFGMDLNKMTHSRLAALRVTKPYLDIGC
• Function: Plays an essential role as an potent mitigator of inflammation. Primarily expressed in dendritic cells and macrophages, inhibits both canonical and non-canonical NF-kappa-B and ERK activation pathways. Functions as a negative regulator of NOD2 by targeting it to degradation via the proteasome pathway. In turn, promotes bacterial tolerance. Inhibits also the RIGI-mediated immune signaling against RNA viruses by reducing the E3 ubiquitin ligase TRIM25-mediated 'Lys-63'-linked RIGI activation but enhancing the E3 ubiquitin ligase RNF125-mediated 'Lys-48'-linked RIGI degradation. Acts also as a negative regulator of inflammatory response to mitigate obesity and obesity-associated diseases in adipose tissue.
• Tissue Specificity: Detected only in peripheral blood leukocytes, predominantly in eosinophils and granulocytes, and at lower levels in monocytes.
• KEGG Pathway: NOD-like receptor sig.ling pathway (hsa04621)
• Reactome Pathway: SARS-CoV-2 activates/modulates innate and adaptive immune responses (R-HSA-9705671)

Molecular Interaction Atlas (MIA) of This DOT

43 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Malaria	DISQ9Y50	Definitive	Altered Expression	[1]
Relapsing fever	DISEA4L7	Definitive	Biomarker	[2]
Adult glioblastoma	DISVP4LU	Strong	Biomarker	[3]
Amyloidosis	DISHTAI2	Strong	Genetic Variation	[4]
Autoinflammatory syndrome	DISCMCGL	Strong	Biomarker	[5]
Autosomal dominant familial periodic fever	DISCRNV1	Strong	Biomarker	[6]
Cataract	DISUD7SL	Strong	Genetic Variation	[7]
Clear cell renal carcinoma	DISBXRFJ	Strong	Biomarker	[8]
Colitis	DISAF7DD	Strong	Biomarker	[9]
Colon cancer	DISVC52G	Strong	Biomarker	[10]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[10]
Common variable immunodeficiency	DISHE7JQ	Strong	Genetic Variation	[4]
Coronary atherosclerosis	DISKNDYU	Strong	Genetic Variation	[11]
Coronary heart disease	DIS5OIP1	Strong	Genetic Variation	[11]
Depression	DIS3XJ69	Strong	Genetic Variation	[11]
Familial cold autoinflammatory syndrome	DISAPE70	Strong	Genetic Variation	[12]
Familial cold autoinflammatory syndrome 2	DISZ2FY1	Strong	Autosomal dominant	[13]
Familial Mediterranean fever	DISVP5WP	Strong	Genetic Variation	[6]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[3]
Glioma	DIS5RPEH	Strong	Altered Expression	[3]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[14]
Hereditary periodic fever syndrome	DISS9RWQ	Strong	Genetic Variation	[15]
Inflammatory bowel disease	DISGN23E	Strong	Genetic Variation	[16]
Muckle-Wells syndrome	DISMT3TQ	Strong	Genetic Variation	[17]
Non-immunoglobulin-mediated membranoproliferative glomerulonephritis	DISLMV1J	Strong	Genetic Variation	[17]
Obesity	DIS47Y1K	Strong	Biomarker	[18]
Papillary renal cell carcinoma	DIS25HBV	Strong	Biomarker	[8]
Periodic fever syndrome	DIS9MNYC	Strong	Biomarker	[19]
Pharyngitis	DISSN548	Strong	Biomarker	[6]
Pneumonia	DIS8EF3M	Strong	Biomarker	[20]
Pneumonitis	DIS88E0K	Strong	Biomarker	[20]
Prostate cancer	DISF190Y	Strong	Biomarker	[21]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[21]
Renal cell carcinoma	DISQZ2X8	Strong	Biomarker	[8]
Ulcerative colitis	DIS8K27O	Strong	Biomarker	[22]
Corneal disease	DISTUIM1	moderate	Altered Expression	[23]
Keratitis	DISMFOEI	moderate	Biomarker	[23]
Alzheimer disease	DISF8S70	Limited	Biomarker	[19]
Alzheimer disease 3	DISVT69G	Limited	Biomarker	[19]
Bacterial infection	DIS5QJ9S	Limited	Biomarker	[24]
Carcinoid syndrome	DISDS5OT	Limited	Genetic Variation	[25]
Stroke	DISX6UHX	Limited	Genetic Variation	[26]
Tuberculosis	DIS2YIMD	Limited	Altered Expression	[27]

3 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 12 (NLRP12).	[28]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of NACHT, LRR and PYD domains-containing protein 12 (NLRP12).	[30]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of NACHT, LRR and PYD domains-containing protein 12 (NLRP12).	[33]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of NACHT, LRR and PYD domains-containing protein 12 (NLRP12).	[29]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of NACHT, LRR and PYD domains-containing protein 12 (NLRP12).	[31]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of NACHT, LRR and PYD domains-containing protein 12 (NLRP12).	[31]
DNCB	DMDTVYC	Phase 2	DNCB decreases the expression of NACHT, LRR and PYD domains-containing protein 12 (NLRP12).	[32]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of NACHT, LRR and PYD domains-containing protein 12 (NLRP12).	[34]

References

• [1] Malaria-induced NLRP12/NLRP3-dependent caspase-1 activation mediates inflammation and hypersensitivity to bacterial superinfection.PLoS Pathog. 2014 Jan;10(1):e1003885. doi: 10.1371/journal.ppat.1003885. Epub 2014 Jan 16.
• [2] The clinical phenotype and genotype of NLRP12-autoinflammatory disease: a Chinese case series with literature review.World J Pediatr. 2020 Oct;16(5):514-519. doi: 10.1007/s12519-019-00294-8. Epub 2019 Dec 9.
• [3] Differential Expression Profile of NLRs and AIM2 in Glioma and Implications for NLRP12 in Glioblastoma.Sci Rep. 2019 Jun 11;9(1):8480. doi: 10.1038/s41598-019-44854-4.
• [4] Novel NLRP12 mutations associated with intestinal amyloidosis in a patient diagnosed with common variable immunodeficiency.Clin Immunol. 2014 Oct;154(2):105-11. doi: 10.1016/j.clim.2014.07.003. Epub 2014 Jul 23.
• [5] Novel Deleterious Sequence Change in the NLRP12 Gene in a Child with the Autoinflammatory Syndrome, Joint Hypermobility and Cutis Laxa from India.Mediterr J Hematol Infect Dis. 2019 Mar 1;11(1):e2019018. doi: 10.4084/MJHID.2019.018. eCollection 2019.
• [6] Phenotypes and genotypes of Chinese adult patients with systemic autoinflammatory diseases.Semin Arthritis Rheum. 2019 Dec;49(3):446-452. doi: 10.1016/j.semarthrit.2019.05.002. Epub 2019 May 11.
• [7] Spontaneously Hypertensive Rat Chromosome 2 with Mutant Connexin 50 Triggers Divergent Effects on Metabolic Syndrome Components.Folia Biol (Praha). 2017;63(2):67-77.
• [8] Integrated molecular analysis of clear-cell renal cell carcinoma.Nat Genet. 2013 Aug;45(8):860-7. doi: 10.1038/ng.2699. Epub 2013 Jun 24.
• [9] NLRP12 attenuates colon inflammation by maintaining colonic microbial diversity and promoting protective commensal bacterial growth.Nat Immunol. 2017 May;18(5):541-551. doi: 10.1038/ni.3690. Epub 2017 Mar 13.
• [10] The multifaceted nature of NLRP12.J Leukoc Biol. 2014 Dec;96(6):991-1000. doi: 10.1189/jlb.3RU0514-265RR. Epub 2014 Sep 23.
• [11] The inflammasome NLRP12 is associated with both depression and coronary artery disease in Vietnam veterans.Psychiatry Res. 2018 Dec;270:775-779. doi: 10.1016/j.psychres.2018.10.051. Epub 2018 Oct 27.
• [12] Identification of a Novel NLRP12 Nonsense Mutation (Trp408X) in the Extremely Rare Disease FCAS by Exome Sequencing.PLoS One. 2016 Jun 17;11(6):e0156981. doi: 10.1371/journal.pone.0156981. eCollection 2016.
• [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] NLRP12 suppresses hepatocellular carcinoma via downregulation of cJun N-terminal kinase activation in the hepatocyte.Elife. 2019 Apr 16;8:e40396. doi: 10.7554/eLife.40396.
• [15] A clinical update on inflammasomopathies.Int Immunol. 2017 Nov 1;29(9):393-400. doi: 10.1093/intimm/dxx020.
• [16] Association between genotypes of rs34436714 of NLRP12 and serum tumor necrosis factor-alpha in inflammatory bowel disease: A case-control study.Medicine (Baltimore). 2019 Jun;98(23):e15913. doi: 10.1097/MD.0000000000015913.
• [17] C3 glomerulopathy in NLRP12-related autoinflammatory disorder: case-based review.Rheumatol Int. 2018 Aug;38(8):1571-1576. doi: 10.1007/s00296-018-4092-3. Epub 2018 Jun 27.
• [18] The Inhibitory Innate Immune Sensor NLRP12 Maintains a Threshold against Obesity by Regulating Gut Microbiota Homeostasis.Cell Host Microbe. 2018 Sep 12;24(3):364-378.e6. doi: 10.1016/j.chom.2018.08.009.
• [19] NLRP12 autoinflammatory disease: a Chinese case series and literature review.Clin Rheumatol. 2017 Jul;36(7):1661-1667. doi: 10.1007/s10067-016-3410-y. Epub 2016 Sep 16.
• [20] Involvement of EGF receptor signaling and NLRP12 inflammasome in fine particulate matter-induced lung inflammation in mice.Environ Toxicol. 2017 Apr;32(4):1121-1134. doi: 10.1002/tox.22308. Epub 2016 Jul 5.
• [21] Expression analysis of inflammasome sensors and implication of NLRP12 inflammasome in prostate cancer.Sci Rep. 2017 Jun 29;7(1):4378. doi: 10.1038/s41598-017-04286-4.
• [22] Gut Microbiota-Mediated NLRP12 Expression Drives the Attenuation of Dextran Sulphate Sodium-Induced Ulcerative Colitis by Qingchang Wenzhong Decoction.Evid Based Complement Alternat Med. 2019 Apr 2;2019:9839474. doi: 10.1155/2019/9839474. eCollection 2019.
• [23] NLRP12 promotes host resistance against Pseudomonas aeruginosa keratitis inflammatory responses through the negative regulation of NF-B signaling.Eur Rev Med Pharmacol Sci. 2018 Dec;22(23):8063-8075. doi: 10.26355/eurrev_201812_16496.
• [24] NLRP12 Attenuates Inflammatory Bone Loss in Experimental Apical Periodontitis.J Dent Res. 2019 Apr;98(4):476-484. doi: 10.1177/0022034518820289. Epub 2019 Jan 25.
• [25] Generalized Cytokine Increase in the Setting of a Multisystem Clinical Disorder and Carcinoid Syndrome Associated with a Novel NLRP12 Variant.Dig Dis Sci. 2019 Aug;64(8):2140-2146. doi: 10.1007/s10620-019-05525-6. Epub 2019 Feb 20.
• [26] Utilizing Whole-Exome Sequencing to Characterize the Phenotypic Variability of Sickle Cell Disease.Genet Test Mol Biomarkers. 2018 Sep;22(9):561-567. doi: 10.1089/gtmb.2018.0058. Epub 2018 Sep 5.
• [27] The CATERPILLER protein monarch-1 is an antagonist of toll-like receptor-, tumor necrosis factor alpha-, and Mycobacterium tuberculosis-induced pro-inflammatory signals.J Biol Chem. 2005 Dec 2;280(48):39914-24. doi: 10.1074/jbc.M502820200. Epub 2005 Oct 3.
• [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] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [30] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [31] Synergistic antiproliferative effect of arsenic trioxide combined with bortezomib in HL60 cell line and primary blasts from patients affected by myeloproliferative disorders. Cancer Genet Cytogenet. 2010 Jun;199(2):110-20. doi: 10.1016/j.cancergencyto.2010.02.010.
• [32] Understanding chemical allergen potency: role of NLRP12 and Blimp-1 in the induction of IL-18 in human keratinocytes. Arch Toxicol. 2017 Apr;91(4):1783-1794. doi: 10.1007/s00204-016-1806-8. Epub 2016 Sep 1.
• [33] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [34] Comparison of transcriptome expression alterations by chronic exposure to low-dose bisphenol A in different subtypes of breast cancer cells. Toxicol Appl Pharmacol. 2019 Dec 15;385:114814. doi: 10.1016/j.taap.2019.114814. Epub 2019 Nov 9.