Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJYU0W8)

• DOT Name: Protein Atg16l2 (ATG16L2)
• Synonyms: APG16-like 2; Autophagy-related protein 16-2; WD repeat-containing protein 80
• Gene Name: ATG16L2
• Related Disease:
  Crohn disease
  Inflammatory bowel disease
  Lung adenocarcinoma
  Multiple sclerosis
  Non-small-cell lung cancer
  Pneumonitis
  Systemic lupus erythematosus
  Kidney cancer
  Renal carcinoma
  Nasopharyngeal carcinoma
  Neoplasm
  Spinocerebellar ataxia type 3
• UniProt ID: A16L2_HUMAN
• Pfam ID: PF08614 ; PF00400
• Sequence:
  MAGPGVPGAPAARWKRHIVRQLRLRDRTQKALFLELVPAYNHLLEKAELLDKFSKKLQPE
  PNSVTPTTHQGPWEESELDSDQVPSLVALRVKWQEEEEGLRLVCGEMAYQVVEKGAALGT
  LESELQQRQSRLAALEARVAQLREARAQQAQQVEEWRAQNAVQRAAYEALRAHVGLREAA
  LRRLQEEARDLLERLVQRKARAAAERNLRNERRERAKQARVSQELKKAAKRTVSISEGPD
  TLGDGMRERRETLALAPEPEPLEKEACEKWKRPFRSASATSLTLSHCVDVVKGLLDFKKR
  RGHSIGGAPEQRYQIIPVCVAARLPTRAQDVLDAHLSEVNAVRFGPNSSLLATGGADRLI
  HLWNVVGSRLEANQTLEGAGGSITSVDFDPSGYQVLAATYNQAAQLWKVGEAQSKETLSG
  HKDKVTAAKFKLTRHQAVTGSRDRTVKEWDLGRAYCSRTINVLSYCNDVVCGDHIIISGH
  NDQKIRFWDSRGPHCTQVIPVQGRVTSLSLSHDQLHLLSCSRDNTLKVIDLRVSNIRQVF
  RADGFKCGSDWTKAVFSPDRSYALAGSCDGALYIWDVDTGKLESRLQGPHCAAVNAVAWC
  YSGSHMVSVDQGRKVVLWQ
• Function: May play a role in regulating epithelial homeostasis in an ATG16L1-dependent manner.
• KEGG Pathway: Autophagy - animal (hsa04140)

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Crohn disease	DIS2C5Q8	Strong	Biomarker	[1]
Inflammatory bowel disease	DISGN23E	Strong	Genetic Variation	[2]
Lung adenocarcinoma	DISD51WR	Strong	Genetic Variation	[3]
Multiple sclerosis	DISB2WZI	Strong	Biomarker	[4]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Genetic Variation	[5]
Pneumonitis	DIS88E0K	Strong	Genetic Variation	[5]
Systemic lupus erythematosus	DISI1SZ7	Strong	Biomarker	[1]
Kidney cancer	DISBIPKM	Disputed	Biomarker	[6]
Renal carcinoma	DISER9XT	Disputed	Biomarker	[6]
Nasopharyngeal carcinoma	DISAOTQ0	Limited	Genetic Variation	[7]
Neoplasm	DISZKGEW	Limited	Genetic Variation	[7]
Spinocerebellar ataxia type 3	DISQBQID	Limited	Altered Expression	[8]

11 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 Protein Atg16l2 (ATG16L2).	[9]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Protein Atg16l2 (ATG16L2).	[10]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Protein Atg16l2 (ATG16L2).	[11]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Protein Atg16l2 (ATG16L2).	[12]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Protein Atg16l2 (ATG16L2).	[13]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Protein Atg16l2 (ATG16L2).	[14]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Protein Atg16l2 (ATG16L2).	[15]
Trovafloxacin	DM6AN32	Approved	Trovafloxacin decreases the expression of Protein Atg16l2 (ATG16L2).	[16]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Protein Atg16l2 (ATG16L2).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Protein Atg16l2 (ATG16L2).	[13]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Protein Atg16l2 (ATG16L2).	[18]

References

• [1] Distinct Tissue-Specific Roles for the Disease-Associated Autophagy Genes ATG16L2 and ATG16L1.J Immunol. 2019 Oct 1;203(7):1820-1829. doi: 10.4049/jimmunol.1800419. Epub 2019 Aug 26.
• [2] Genetic characteristics of inflammatory bowel disease in a Japanese population.J Gastroenterol. 2016 Jul;51(7):672-81. doi: 10.1007/s00535-015-1135-3. Epub 2015 Oct 28.
• [3] Clinical Implications of the Autophagy Core Gene Variations in Advanced Lung Adenocarcinoma Treated with Gefitinib.Sci Rep. 2017 Dec 19;7(1):17814. doi: 10.1038/s41598-017-18165-5.
• [4] Autophagy-related gene16L2, a potential serum biomarker of multiple sclerosis evaluated by bead-based proteomic technology.Neurosci Lett. 2014 Mar 6;562:34-8. doi: 10.1016/j.neulet.2013.12.070. Epub 2014 Jan 7.
• [5] Potentially Functional Variants of ATG16L2 Predict Radiation Pneumonitis and Outcomes in Patients with Non-Small Cell Lung Cancer after Definitive Radiotherapy.J Thorac Oncol. 2018 May;13(5):660-675. doi: 10.1016/j.jtho.2018.01.028. Epub 2018 Feb 15.
• [6] Cross-cancer profiling of molecular alterations within the human autophagy interaction network.Autophagy. 2015;11(9):1668-87. doi: 10.1080/15548627.2015.1067362.
• [7] Potentially functional variants of autophagy-related genes are associated with the efficacy and toxicity of radiotherapy in patients with nasopharyngeal carcinoma.Mol Genet Genomic Med. 2019 Dec;7(12):e1030. doi: 10.1002/mgg3.1030. Epub 2019 Nov 6.
• [8] Deregulation of autophagy in postmortem brains of Machado-Joseph disease patients.Neuropathology. 2018 Apr;38(2):113-124. doi: 10.1111/neup.12433. Epub 2017 Dec 8.
• [9] 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.
• [10] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [11] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [12] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [13] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [14] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [15] Functional gene expression profile underlying methotrexate-induced senescence in human colon cancer cells. Tumour Biol. 2011 Oct;32(5):965-76.
• [16] TNF enhances trovafloxacin-induced in vitro hepatotoxicity by inhibiting protective autophagy. Toxicol Lett. 2021 May 15;342:73-84. doi: 10.1016/j.toxlet.2021.02.009. Epub 2021 Feb 17.
• [17] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [18] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.