Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTEOYC5D)

DOT Name Autophagy-related protein 16-1 (ATG16L1)
Synonyms APG16-like 1
Gene Name ATG16L1
Related Disease
Arteriosclerosis ( )
Atherosclerosis ( )
Bacterial infection ( )
Coeliac disease ( )
Colorectal carcinoma ( )
Hepatocellular carcinoma ( )
Intestinal disorder ( )
Lung cancer ( )
Lung carcinoma ( )
Multiple sclerosis ( )
Mycobacterium infection ( )
Neoplasm ( )
Non-small-cell lung cancer ( )
Prostate cancer ( )
Prostate carcinoma ( )
Rheumatoid arthritis ( )
Systemic lupus erythematosus ( )
Tuberculosis ( )
Asthma ( )
Autoimmune disease, susceptibility to, 6 ( )
Autoimmune thyroid disease ( )
Common variable immunodeficiency ( )
Gastric cancer ( )
Head-neck squamous cell carcinoma ( )
Inflammation ( )
Juvenile idiopathic arthritis ( )
Obesity ( )
Squamous cell carcinoma ( )
STAT3-related early-onset multisystem autoimmune disease ( )
Stomach cancer ( )
Type-1 diabetes ( )
Ulcerative colitis ( )
Advanced cancer ( )
Ankylosing spondylitis ( )
Autoimmune disease ( )
Bone osteosarcoma ( )
Colitis ( )
Cowden disease ( )
Hepatitis C virus infection ( )
Irritable bowel syndrome ( )
Melanoma ( )
Osteosarcoma ( )
Psoriasis ( )
Sclerosing cholangitis ( )
UniProt ID
A16L1_HUMAN
3D Structure
Download
2D Sequence (FASTA)
Download
3D Structure (PDB)
Download
PDB ID
4GDK; 4GDL; 4NAW; 4TQ0; 5D7G; 5NPV; 5NPW; 5NUV; 5ZYX; 7F69; 7W36; 7XFR
Pfam ID
PF08614 ; PF00400
Sequence
MSSGLRAADFPRWKRHISEQLRRRDRLQRQAFEEIILQYNKLLEKSDLHSVLAQKLQAEK
HDVPNRHEISPGHDGTWNDNQLQEMAQLRIKHQEELTELHKKRGELAQLVIDLNNQMQRK
DREMQMNEAKIAECLQTISDLETECLDLRTKLCDLERANQTLKDEYDALQITFTALEGKL
RKTTEENQELVTRWMAEKAQEANRLNAENEKDSRRRQARLQKELAEAAKEPLPVEQDDDI
EVIVDETSDHTEETSPVRAISRAATKRLSQPAGGLLDSITNIFGRRSVSSFPVPQDNVDT
HPGSGKEVRVPATALCVFDAHDGEVNAVQFSPGSRLLATGGMDRRVKLWEVFGEKCEFKG
SLSGSNAGITSIEFDSAGSYLLAASNDFASRIWTVDDYRLRHTLTGHSGKVLSAKFLLDN
ARIVSGSHDRTLKLWDLRSKVCIKTVFAGSSCNDIVCTEQCVMSGHFDKKIRFWDIRSES
IVREMELLGKITALDLNPERTELLSCSRDDLLKVIDLRTNAIKQTFSAPGFKCGSDWTRV
VFSPDGSYVAAGSAEGSLYIWSVLTGKVEKVLSKQHSSSINAVAWSPSGSHVVSVDKGCK
AVLWAQY
Function
Plays an essential role in both canonical and non-canonical autophagy: interacts with ATG12-ATG5 to mediate the lipidation to ATG8 family proteins (MAP1LC3A, MAP1LC3B, MAP1LC3C, GABARAPL1, GABARAPL2 and GABARAP). Acts as a molecular hub, coordinating autophagy pathways via distinct domains that support either canonical or non-canonical signaling. During canonical autophagy, interacts with ATG12-ATG5 to mediate the conjugation of phosphatidylethanolamine (PE) to ATG8 proteins, to produce a membrane-bound activated form of ATG8. Thereby, controls the elongation of the nascent autophagosomal membrane. Also involved in non-canonical autophagy, a parallel pathway involving conjugation of ATG8 proteins to single membranes at endolysosomal compartments, probably by catalyzing conjugation of phosphatidylserine (PS) to ATG8. Non-canonical autophagy plays a key role in epithelial cells to limit lethal infection by influenza A (IAV) virus. Regulates mitochondrial antiviral signaling (MAVS)-dependent type I interferon (IFN-I) production. Negatively regulates NOD1- and NOD2-driven inflammatory cytokine response. Instead, promotes an autophagy-dependent antibacterial pathway together with NOD1 or NOD2. Plays a role in regulating morphology and function of Paneth cell.
KEGG Pathway
Autophagy - other (hsa04136 )
Autophagy - animal (hsa04140 )
NOD-like receptor sig.ling pathway (hsa04621 )
Shigellosis (hsa05131 )
Reactome Pathway
Macroautophagy (R-HSA-1632852 )

Molecular Interaction Atlas (MIA) of This DOT

44 Disease(s) Related to This DOT
Disease Name Disease ID Evidence Level Mode of Inheritance REF
Arteriosclerosis DISK5QGC Strong Biomarker [1]
Atherosclerosis DISMN9J3 Strong Biomarker [1]
Bacterial infection DIS5QJ9S Strong Biomarker [2]
Coeliac disease DISIY60C Strong Genetic Variation [3]
Colorectal carcinoma DIS5PYL0 Strong Genetic Variation [4]
Hepatocellular carcinoma DIS0J828 Strong Genetic Variation [5]
Intestinal disorder DISGPMUQ Strong Genetic Variation [6]
Lung cancer DISCM4YA Strong Genetic Variation [7]
Lung carcinoma DISTR26C Strong Genetic Variation [7]
Multiple sclerosis DISB2WZI Strong Genetic Variation [8]
Mycobacterium infection DISNSMUD Strong Genetic Variation [9]
Neoplasm DISZKGEW Strong Genetic Variation [10]
Non-small-cell lung cancer DIS5Y6R9 Strong Genetic Variation [7]
Prostate cancer DISF190Y Strong Biomarker [11]
Prostate carcinoma DISMJPLE Strong Biomarker [11]
Rheumatoid arthritis DISTSB4J Strong Biomarker [12]
Systemic lupus erythematosus DISI1SZ7 Strong Biomarker [13]
Tuberculosis DIS2YIMD Strong Biomarker [12]
Asthma DISW9QNS moderate Genetic Variation [14]
Autoimmune disease, susceptibility to, 6 DISHNUXI moderate Genetic Variation [3]
Autoimmune thyroid disease DISIHC6A moderate Genetic Variation [3]
Common variable immunodeficiency DISHE7JQ moderate Genetic Variation [3]
Gastric cancer DISXGOUK moderate Biomarker [15]
Head-neck squamous cell carcinoma DISF7P24 moderate Genetic Variation [16]
Inflammation DISJUQ5T moderate Genetic Variation [17]
Juvenile idiopathic arthritis DISQZGBV moderate Genetic Variation [3]
Obesity DIS47Y1K moderate Biomarker [18]
Squamous cell carcinoma DISQVIFL moderate Biomarker [19]
STAT3-related early-onset multisystem autoimmune disease DISAXTN7 moderate Genetic Variation [3]
Stomach cancer DISKIJSX moderate Biomarker [15]
Type-1 diabetes DIS7HLUB moderate Genetic Variation [3]
Ulcerative colitis DIS8K27O moderate Genetic Variation [20]
Advanced cancer DISAT1Z9 Limited Biomarker [21]
Ankylosing spondylitis DISRC6IR Limited Genetic Variation [22]
Autoimmune disease DISORMTM Limited Biomarker [23]
Bone osteosarcoma DIST1004 Limited Altered Expression [24]
Colitis DISAF7DD Limited Biomarker [25]
Cowden disease DISMYKCE Limited Genetic Variation [26]
Hepatitis C virus infection DISQ0M8R Limited Biomarker [27]
Irritable bowel syndrome DIS27206 Limited Genetic Variation [6]
Melanoma DIS1RRCY Limited Altered Expression [28]
Osteosarcoma DISLQ7E2 Limited Altered Expression [24]
Psoriasis DIS59VMN Limited Genetic Variation [29]
Sclerosing cholangitis DIS7GZNB Limited Genetic Variation [29]
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⏷ Show the Full List of 44 Disease(s)
Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
11 Drug(s) Affected the Gene/Protein Processing of This DOT
Drug Name Drug ID Highest Status Interaction REF
Valproate DMCFE9I Approved Valproate increases the expression of Autophagy-related protein 16-1 (ATG16L1). [30]
Ciclosporin DMAZJFX Approved Ciclosporin increases the expression of Autophagy-related protein 16-1 (ATG16L1). [31]
Acetaminophen DMUIE76 Approved Acetaminophen increases the expression of Autophagy-related protein 16-1 (ATG16L1). [32]
Doxorubicin DMVP5YE Approved Doxorubicin decreases the expression of Autophagy-related protein 16-1 (ATG16L1). [33]
Cupric Sulfate DMP0NFQ Approved Cupric Sulfate increases the expression of Autophagy-related protein 16-1 (ATG16L1). [34]
Methotrexate DM2TEOL Approved Methotrexate increases the expression of Autophagy-related protein 16-1 (ATG16L1). [35]
Melphalan DMOLNHF Approved Melphalan increases the expression of Autophagy-related protein 16-1 (ATG16L1). [37]
Trovafloxacin DM6AN32 Approved Trovafloxacin increases the expression of Autophagy-related protein 16-1 (ATG16L1). [38]
Milchsaure DM462BT Investigative Milchsaure decreases the expression of Autophagy-related protein 16-1 (ATG16L1). [39]
acrolein DMAMCSR Investigative acrolein increases the expression of Autophagy-related protein 16-1 (ATG16L1). [41]
Galangin DM5TQ2O Investigative Galangin increases the expression of Autophagy-related protein 16-1 (ATG16L1). [42]
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⏷ Show the Full List of 11 Drug(s)
3 Drug(s) Affected the Post-Translational Modifications of This DOT
Drug Name Drug ID Highest Status Interaction REF
Fulvestrant DM0YZC6 Approved Fulvestrant increases the methylation of Autophagy-related protein 16-1 (ATG16L1). [36]
Bisphenol A DM2ZLD7 Investigative Bisphenol A increases the methylation of Autophagy-related protein 16-1 (ATG16L1). [36]
Coumarin DM0N8ZM Investigative Coumarin affects the phosphorylation of Autophagy-related protein 16-1 (ATG16L1). [40]
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References

1 ATG16L1 Expression in Carotid Atherosclerotic Plaques Is Associated With Plaque Vulnerability.Arterioscler Thromb Vasc Biol. 2015 May;35(5):1226-35. doi: 10.1161/ATVBAHA.114.304840. Epub 2015 Mar 12.
2 The T300A Crohn's disease risk polymorphism impairs function of the WD40 domain of ATG16L1.Nat Commun. 2016 Jun 8;7:11821. doi: 10.1038/ncomms11821.
3 Meta-analysis of shared genetic architecture across ten pediatric autoimmune diseases.Nat Med. 2015 Sep;21(9):1018-27. doi: 10.1038/nm.3933. Epub 2015 Aug 24.
4 The Thr300Ala variant in ATG16L1 is associated with improved survival in human colorectal cancer and enhanced production of type I interferon.Gut. 2016 Mar;65(3):456-64. doi: 10.1136/gutjnl-2014-308735. Epub 2015 Feb 2.
5 The ATG16L1 gene variant rs2241880 (p.T300A) is associated with susceptibility to HCC in patients with cirrhosis.Liver Int. 2019 Dec;39(12):2360-2367. doi: 10.1111/liv.14239. Epub 2019 Sep 11.
6 Protein tyrosine phosphatase nonreceptor type 2 regulates autophagosome formation in human intestinal cells.Inflamm Bowel Dis. 2012 Jul;18(7):1287-302. doi: 10.1002/ibd.21891. Epub 2011 Oct 10.
7 The Thr300Ala variant of ATG16L1 is associated with decreased risk of brain metastasis in patients with non-small cell lung cancer.Autophagy. 2017 Jun 3;13(6):1053-1063. doi: 10.1080/15548627.2017.1308997. Epub 2017 Apr 25.
8 Genome-wide meta-analysis identifies novel multiple sclerosis susceptibility loci.Ann Neurol. 2011 Dec;70(6):897-912. doi: 10.1002/ana.22609.
9 Genetic Variation in Autophagy-Related Genes Influences the Risk and Phenotype of Buruli Ulcer.PLoS Negl Trop Dis. 2016 Apr 29;10(4):e0004671. doi: 10.1371/journal.pntd.0004671. eCollection 2016 Apr.
10 ATG5 cancer mutations and alternative mRNA splicing reveal a conjugation switch that regulates ATG12-ATG5-ATG16L1 complex assembly and autophagy.Cell Discov. 2019 Aug 27;5:42. doi: 10.1038/s41421-019-0110-1. eCollection 2019.
11 Dynamics of Atg5-Atg12-Atg16L1 Aggregation and Deaggregation.Methods Enzymol. 2017;587:247-255. doi: 10.1016/bs.mie.2016.09.059. Epub 2016 Dec 3.
12 Mir223 restrains autophagy and promotes CNS inflammation by targeting ATG16L1.Autophagy. 2019 Mar;15(3):478-492. doi: 10.1080/15548627.2018.1522467. Epub 2018 Sep 22.
13 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.
14 Association between ORMDL3, IL1RL1 and a deletion on chromosome 17q21 with asthma risk in Australia.Eur J Hum Genet. 2011 Apr;19(4):458-64. doi: 10.1038/ejhg.2010.191. Epub 2010 Dec 8.
15 miR-874 regulates multiple-drug resistance in gastric cancer by targeting ATG16L1.Int J Oncol. 2018 Dec;53(6):2769-2779. doi: 10.3892/ijo.2018.4593. Epub 2018 Oct 11.
16 ATG12 expression quantitative trait loci associated with head and neck squamous cell carcinoma risk in a Chinese Han population.Mol Carcinog. 2018 Aug;57(8):1030-1037. doi: 10.1002/mc.22823. Epub 2018 Apr 24.
17 An ATG16L1-dependent pathway promotes plasma membrane repair and limits Listeria monocytogenes cell-to-cell spread.Nat Microbiol. 2018 Dec;3(12):1472-1485. doi: 10.1038/s41564-018-0293-5. Epub 2018 Nov 26.
18 Myeloid ATG16L1 does not affect adipose tissue inflammation or body mass in mice fed high fat diet.Obes Res Clin Pract. 2018 Mar-Apr;12(2):174-186. doi: 10.1016/j.orcp.2017.10.006. Epub 2017 Nov 2.
19 Overexpression of autophagy-related 16-like 1 in patients with oral squamous cell carcinoma.Pathol Oncol Res. 2015 Apr;21(2):301-5. doi: 10.1007/s12253-014-9821-7. Epub 2014 Jul 25.
20 The ATG16L1 risk allele associated with Crohn's disease results in a Rac1-dependent defect in dendritic cell migration that is corrected by thiopurines.Mucosal Immunol. 2017 Mar;10(2):352-360. doi: 10.1038/mi.2016.65. Epub 2016 Jul 20.
21 An Integrative Systems Biology and Experimental Approach Identifies Convergence of Epithelial Plasticity, Metabolism, and Autophagy to Promote Chemoresistance.J Clin Med. 2019 Feb 7;8(2):205. doi: 10.3390/jcm8020205.
22 Single nucleotide polymorphisms of autophagy-related 16-like 1 gene are associated with ankylosing spondylitis in females: a case-control study.Int J Rheum Dis. 2018 Jan;21(1):322-329. doi: 10.1111/1756-185X.13183. Epub 2017 Sep 26.
23 miR-142-3p regulates autophagy by targeting ATG16L1 in thymic-derived regulatory T cell (tTreg).Cell Death Dis. 2018 Feb 19;9(3):290. doi: 10.1038/s41419-018-0298-2.
24 MicroRNA-410 regulates autophagy-related gene ATG16L1 expression and enhances chemosensitivity via autophagy inhibition in osteosarcoma.Mol Med Rep. 2017 Mar;15(3):1326-1334. doi: 10.3892/mmr.2017.6149. Epub 2017 Jan 26.
25 The protection role of Atg16l1 in CD11c(+)dendritic cells in murine colitis.Immunobiology. 2017 Jul;222(7):831-841. doi: 10.1016/j.imbio.2017.03.002. Epub 2017 Mar 16.
26 NOD2 and ATG16L1 polymorphisms affect monocyte responses in Crohn's disease.World J Gastroenterol. 2011 Jun 21;17(23):2829-37. doi: 10.3748/wjg.v17.i23.2829.
27 LC3B is not recruited along with the autophagy elongation complex (ATG5-12/16L1) at HCV replication site and is dispensable for viral replication.PLoS One. 2018 Oct 4;13(10):e0205189. doi: 10.1371/journal.pone.0205189. eCollection 2018.
28 Variants in autophagy-related genes and clinical characteristics in melanoma: a population-based study.Cancer Med. 2016 Nov;5(11):3336-3345. doi: 10.1002/cam4.929. Epub 2016 Oct 17.
29 Analysis of five chronic inflammatory diseases identifies 27 new associations and highlights disease-specific patterns at shared loci.Nat Genet. 2016 May;48(5):510-8. doi: 10.1038/ng.3528. Epub 2016 Mar 14.
30 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.
31 Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
32 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.
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 Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
35 Functional gene expression profile underlying methotrexate-induced senescence in human colon cancer cells. Tumour Biol. 2011 Oct;32(5):965-76.
36 DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
37 Bone marrow osteoblast damage by chemotherapeutic agents. PLoS One. 2012;7(2):e30758. doi: 10.1371/journal.pone.0030758. Epub 2012 Feb 17.
38 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.
39 Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
40 Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
41 Acrolein induces NLRP3 inflammasome-mediated pyroptosis and suppresses migration via ROS-dependent autophagy in vascular endothelial cells. Toxicology. 2018 Dec 1;410:26-40. doi: 10.1016/j.tox.2018.09.002. Epub 2018 Sep 8.
42 Galangin suppresses HepG2 cell proliferation by activating the TGF- receptor/Smad pathway. Toxicology. 2014 Dec 4;326:9-17. doi: 10.1016/j.tox.2014.09.010. Epub 2014 Sep 28.