Details of Drug Off-Target (DOT)

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

• DOT Name: NLR family CARD domain-containing protein 3 (NLRC3)
• Synonyms: CARD15-like protein; Caterpiller protein 16.2; CLR16.2; NACHT, LRR and CARD domains-containing protein 3; Nucleotide-binding oligomerization domain protein 3
• Gene Name: NLRC3
• Related Disease:
  Metabolic disorder
  Autoimmune disease
  Colorectal carcinoma
  Hepatocellular carcinoma
  Herpes simplex infection
  High blood pressure
  Keratitis
  Latent tuberculosis infection
  Neoplasm
  Psoriatic arthritis
  Tuberculosis
  Osteoarthritis
  Rheumatoid arthritis
  Advanced cancer
• UniProt ID: NLRC3_HUMAN
• Pfam ID: PF13516 ; PF05729 ; PF17776 ; PF17779
• Sequence:
  MRKQEVRTGREAGQGHGTGSPAEQVKALMDLLAGKGSQGSQAPQALDRTPDAPLGPCSND
  SRIQRHRKALLSKVGGGPELGGPWHRLASLLLVEGLTDLQLREHDFTQVEATRGGGHPAR
  TVALDRLFLPLSRVSVPPRVSITIGVAGMGKTTLVRHFVRLWAHGQVGKDFSLVLPLTFR
  DLNTHEKLCADRLICSVFPHVGEPSLAVAVPARALLILDGLDECRTPLDFSNTVACTDPK
  KEIPVDHLITNIIRGNLFPEVSIWITSRPSASGQIPGGLVDRMTEIRGFNEEEIKVCLEQ
  MFPEDQALLGWMLSQVQADRALYLMCTVPAFCRLTGMALGHLWRSRTGPQDAELWPPRTL
  CELYSWYFRMALSGEGQEKGKASPRIEQVAHGGRKMVGTLGRLAFHGLLKKKYVFYEQDM
  KAFGVDLALLQGAPCSCFLQREETLASSVAYCFTHLSLQEFVAAAYYYGASRRAIFDLFT
  ESGVSWPRLGFLTHFRSAAQRAMQAEDGRLDVFLRFLSGLLSPRVNALLAGSLLAQGEHQ
  AYRTQVAELLQGCLRPDAAVCARAINVLHCLHELQHTELARSVEEAMESGALARLTGPAH
  RAALAYLLQVSDACAQEANLSLSLSQGVLQSLLPQLLYCRKLRLDTNQFQDPVMELLGSV
  LSGKDCRIQKISLAENQISNKGAKALARSLLVNRSLTSLDLRGNSIGPQGAKALADALKI
  NRTLTSLSLQGNTVRDDGARSMAEALASNRTLSMLHLQKNSIGPMGAQRMADALKQNRSL
  KELMFSSNSIGDGGAKALAEALKVNQGLESLDLQSNSISDAGVAALMGALCTNQTLLSLS
  LRENSISPEGAQAIAHALCANSTLKNLDLTANLLHDQGARAIAVAVRENRTLTSLHLQWN
  FIQAGAAQALGQALQLNRSLTSLDLQENAIGDDGACAVARALKVNTALTALYLQVASIGA
  SGAQVLGEALAVNRTLEILDLRGNAIGVAGAKALANALKVNSSLRRLNLQENSLGMDGAI
  CIATALSGNHRLQHINLQGNHIGDSGARMISEAIKTNAPTCTVEM
• Function: Negative regulator of the innate immune response. Attenuates signaling pathways activated by Toll-like receptors (TLRs) and the DNA sensor STING/TMEM173 in response to pathogen-associated molecular patterns, such as intracellular poly(dA:dT), but not poly(I:C), or in response to DNA virus infection, including that of Herpes simplex virus 1 (HSV1). May affect TLR4 signaling by acting at the level of TRAF6 ubiquitination, decreasing the activating 'Lys-63'-linked ubiquitination and leaving unchanged the degradative 'Lys-48'-linked ubiquitination. Inhibits the PI3K-AKT-mTOR pathway possibly by directly interacting with the posphatidylinositol 3-kinase regulatory subunit p85 (PIK3R1/PIK3R2) and disrupting the association between PIK3R1/PIK3R2 and the catalytic subunit p110 (PIK3CA/PIK3CB/PIK3CD) and reducing PIK3R1/PIK3R2 activation. Via its regulation of the PI3K-AKT-mTOR pathway, controls cell proliferation, predominantly in intestinal epithelial cells. May also affect NOD1- or NOD2-mediated NF-kappa-B activation. Might also affect the inflammatory response by preventing NLRP3 inflammasome formation, CASP1 cleavage and IL1B maturation.
• Reactome Pathway: IRF3-mediated induction of type I IFN (R-HSA-3270619)

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Metabolic disorder	DIS71G5H	Definitive	Biomarker	[1]
Autoimmune disease	DISORMTM	Strong	Biomarker	[2]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[3]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[4]
Herpes simplex infection	DISL1SAV	Strong	Biomarker	[5]
High blood pressure	DISY2OHH	Strong	Biomarker	[6]
Keratitis	DISMFOEI	Strong	Biomarker	[7]
Latent tuberculosis infection	DIS6R1EH	Strong	Biomarker	[8]
Neoplasm	DISZKGEW	Strong	Altered Expression	[4]
Psoriatic arthritis	DISLWTG2	Strong	Biomarker	[7]
Tuberculosis	DIS2YIMD	Strong	Biomarker	[8]
Osteoarthritis	DIS05URM	moderate	Biomarker	[9]
Rheumatoid arthritis	DISTSB4J	moderate	Biomarker	[9]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[6]

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 NLR family CARD domain-containing protein 3 (NLRC3).	[10]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of NLR family CARD domain-containing protein 3 (NLRC3).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of NLR family CARD domain-containing protein 3 (NLRC3).	[12]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of NLR family CARD domain-containing protein 3 (NLRC3).	[13]

References

• [1] Hyperuricemia-induced NLRP3 activation of macrophages contributes to the progression of diabetic nephropathy.Am J Physiol Renal Physiol. 2015 May 1;308(9):F993-F1003. doi: 10.1152/ajprenal.00637.2014. Epub 2015 Jan 28.
• [2] The Innate Immune Sensor NLRC3 Acts as a Rheostat that Fine-Tunes T Cell Responses in Infection and Autoimmunity.Immunity. 2018 Dec 18;49(6):1049-1061.e6. doi: 10.1016/j.immuni.2018.10.008.
• [3] NLRC3 regulates cellular proliferation and apoptosis to attenuate the development of colorectal cancer.Cell Cycle. 2017 Jul 3;16(13):1243-1251. doi: 10.1080/15384101.2017.1317414. Epub 2017 Jun 9.
• [4] The correlation of NLRC3 expression with the progression and prognosis of hepatocellular carcinoma.Hum Pathol. 2018 Dec;82:273-281. doi: 10.1016/j.humpath.2018.07.031. Epub 2018 Aug 4.
• [5] NLRC3, a member of the NLR family of proteins, is a negative regulator of innate immune signaling induced by the DNA sensor STING.Immunity. 2014 Mar 20;40(3):329-41. doi: 10.1016/j.immuni.2014.01.010. Epub 2014 Feb 20.
• [6] NLRC3 inhibits MCT-induced pulmonary hypertension in rats via attenuating PI3K activation.J Cell Physiol. 2019 Sep;234(9):15963-15976. doi: 10.1002/jcp.28255. Epub 2019 Feb 14.
• [7] NLRC3 promotes host resistance against Pseudomonas aeruginosa-induced keratitis by promoting the degradation of IRAK1.Int J Mol Med. 2017 Sep;40(3):898-906. doi: 10.3892/ijmm.2017.3077. Epub 2017 Jul 20.
• [8] NLRC3 negatively regulates CD4+ T cells and impacts protective immunity during Mycobacterium tuberculosis infection.PLoS Pathog. 2018 Aug 22;14(8):e1007266. doi: 10.1371/journal.ppat.1007266. eCollection 2018 Aug.
• [9] Differential expressions of NOD-like receptors and their associations with inflammatory responses in rheumatoid arthritis.Clin Exp Rheumatol. 2017 Jul-Aug;35(4):630-637. Epub 2017 Feb 24.
• [10] 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.
• [11] 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.
• [12] 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.
• [13] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.