Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQ4RNRM)

• DOT Name: Cysteine protease ATG4B (ATG4B)
• Synonyms: EC 3.4.22.-; AUT-like 1 cysteine endopeptidase; Autophagy-related cysteine endopeptidase 1; Autophagin-1; Autophagy-related protein 4 homolog B; HsAPG4B; hAPG4B
• Gene Name: ATG4B
• Related Disease:
  Bone osteosarcoma
  Osteosarcoma
  Type-1/2 diabetes
  Alzheimer disease
  Colon cancer
  Colon carcinoma
  Colorectal carcinoma
  Ewing sarcoma
  Hepatocellular carcinoma
  Neoplasm
  Prostate cancer
  Prostate carcinoma
  Pulmonary fibrosis
  Adult glioblastoma
  Childhood kidney Wilms tumor
  Glioblastoma multiforme
  Wilms tumor
  Advanced cancer
  Amyotrophic lateral sclerosis
  Bacterial infection
  Enterovirus infection
  Hand, foot and mouth disease
  Hyperglycemia
  Lung cancer
  Lung carcinoma
  Lung neoplasm
  Squamous cell carcinoma
• UniProt ID: ATG4B_HUMAN
• PDB ID: 2CY7; 2D1I; 2Z0D; 2Z0E; 2ZZP; 5LXH; 5LXI
• EC Number: 3.4.22.-
• Pfam ID: PF20166 ; PF03416
• Sequence:
  MDAATLTYDTLRFAEFEDFPETSEPVWILGRKYSIFTEKDEILSDVASRLWFTYRKNFPA
  IGGTGPTSDTGWGCMLRCGQMIFAQALVCRHLGRDWRWTQRKRQPDSYFSVLNAFIDRKD
  SYYSIHQIAQMGVGEGKSIGQWYGPNTVAQVLKKLAVFDTWSSLAVHIAMDNTVVMEEIR
  RLCRTSVPCAGATAFPADSDRHCNGFPAGAEVTNRPSPWRPLVLLIPLRLGLTDINEAYV
  ETLKHCFMMPQSLGVIGGKPNSAHYFIGYVGEELIYLDPHTTQPAVEPTDGCFIPDESFH
  CQHPPCRMSIAELDPSIAVGFFCKTEDDFNDWCQQVKKLSLLGGALPMFELVELQPSHLA
  CPDVLNLSLDSSDVERLERFFDSEDEDFEILSL
• Function: Cysteine protease that plays a key role in autophagy by mediating both proteolytic activation and delipidation of ATG8 family proteins. Required for canonical autophagy (macroautophagy), non-canonical autophagy as well as for mitophagy. The protease activity is required for proteolytic activation of ATG8 family proteins: cleaves the C-terminal amino acid of ATG8 proteins MAP1LC3A, MAP1LC3B, MAP1LC3C, GABARAPL1, GABARAPL2 and GABARAP, to reveal a C-terminal glycine. Exposure of the glycine at the C-terminus is essential for ATG8 proteins conjugation to phosphatidylethanolamine (PE) and insertion to membranes, which is necessary for autophagy. Protease activity is also required to counteract formation of high-molecular weight conjugates of ATG8 proteins (ATG8ylation): acts as a deubiquitinating-like enzyme that removes ATG8 conjugated to other proteins, such as ATG3. In addition to the protease activity, also mediates delipidation of ATG8 family proteins. Catalyzes delipidation of PE-conjugated forms of ATG8 proteins during macroautophagy. Also involved in non-canonical autophagy, a parallel pathway involving conjugation of ATG8 proteins to single membranes at endolysosomal compartments, by catalyzing delipidation of ATG8 proteins conjugated to phosphatidylserine (PS). Compared to other members of the family (ATG4A, ATG4C or ATG4C), constitutes the major protein for proteolytic activation of ATG8 proteins, while it displays weaker delipidation activity than other ATG4 paralogs. Involved in phagophore growth during mitophagy independently of its protease activity and of ATG8 proteins: acts by regulating ATG9A trafficking to mitochondria and promoting phagophore-endoplasmic reticulum contacts during the lipid transfer phase of mitophagy.
• KEGG Pathway:
  Autophagy - other (hsa04136)
  Autophagy - animal (hsa04140)
• Reactome Pathway: Macroautophagy (R-HSA-1632852)

Molecular Interaction Atlas (MIA) of This DOT

27 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bone osteosarcoma	DIST1004	Definitive	Biomarker	[1]
Osteosarcoma	DISLQ7E2	Definitive	Biomarker	[1]
Type-1/2 diabetes	DISIUHAP	Definitive	Altered Expression	[2]
Alzheimer disease	DISF8S70	Strong	Biomarker	[3]
Colon cancer	DISVC52G	Strong	Biomarker	[4]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[4]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[5]
Ewing sarcoma	DISQYLV3	Strong	Biomarker	[6]
Hepatocellular carcinoma	DIS0J828	Strong	Posttranslational Modification	[7]
Neoplasm	DISZKGEW	Strong	Altered Expression	[8]
Prostate cancer	DISF190Y	Strong	Biomarker	[9]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[9]
Pulmonary fibrosis	DISQKVLA	Strong	Biomarker	[10]
Adult glioblastoma	DISVP4LU	Disputed	Biomarker	[11]
Childhood kidney Wilms tumor	DIS0NMK3	Disputed	Altered Expression	[12]
Glioblastoma multiforme	DISK8246	Disputed	Biomarker	[11]
Wilms tumor	DISB6T16	Disputed	Altered Expression	[12]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[13]
Amyotrophic lateral sclerosis	DISF7HVM	Limited	Altered Expression	[14]
Bacterial infection	DIS5QJ9S	Limited	Altered Expression	[15]
Enterovirus infection	DISH2UDP	Limited	Altered Expression	[16]
Hand, foot and mouth disease	DISKJHLL	Limited	Altered Expression	[16]
Hyperglycemia	DIS0BZB5	Limited	Biomarker	[17]
Lung cancer	DISCM4YA	Limited	Altered Expression	[18]
Lung carcinoma	DISTR26C	Limited	Altered Expression	[18]
Lung neoplasm	DISVARNB	Limited	Altered Expression	[18]
Squamous cell carcinoma	DISQVIFL	Limited	Altered Expression	[19]

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 Cysteine protease ATG4B (ATG4B).	[20]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Cysteine protease ATG4B (ATG4B).	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Cysteine protease ATG4B (ATG4B).	[21]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Cysteine protease ATG4B (ATG4B).	[22]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Cysteine protease ATG4B (ATG4B).	[23]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Cysteine protease ATG4B (ATG4B).	[25]
Sodium phenylbutyrate	DMXLBCQ	Approved	Sodium phenylbutyrate decreases the expression of Cysteine protease ATG4B (ATG4B).	[26]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Cysteine protease ATG4B (ATG4B).	[27]
Curcumin	DMQPH29	Phase 3	Curcumin decreases the expression of Cysteine protease ATG4B (ATG4B).	[26]

References

• [1] SNHG16 promotes osteosarcoma progression and enhances cisplatin resistance by sponging miR-16 to upregulate ATG4B expression.Biochem Biophys Res Commun. 2019 Oct 8;518(1):127-133. doi: 10.1016/j.bbrc.2019.08.019. Epub 2019 Aug 16.
• [2] MiR-34c Participates in Diabetic Corneal Neuropathy Via Regulation of Autophagy.Invest Ophthalmol Vis Sci. 2019 Jan 2;60(1):16-25. doi: 10.1167/iovs.18-24968.
• [3] Down-regulated TMED10 in Alzheimer disease induces autophagy via ATG4B activation.Autophagy. 2019 Sep;15(9):1495-1505. doi: 10.1080/15548627.2019.1586249. Epub 2019 Mar 19.
• [4] lncRNA KCNQ1OT1 enhances the chemoresistance of oxaliplatin in colon cancer by targeting the miR-34a/ATG4B pathway.Onco Targets Ther. 2019 Apr 9;12:2649-2660. doi: 10.2147/OTT.S188054. eCollection 2019.
• [5] Discovery of a small molecule targeting autophagy via ATG4B inhibition and cell death of colorectal cancer cells in vitro and in vivo.Autophagy. 2019 Feb;15(2):295-311. doi: 10.1080/15548627.2018.1517073. Epub 2018 Sep 20.
• [6] EWS-FLI1 positively regulates autophagy by increasing ATG4B expression in Ewing sarcoma cells.Int J Mol Med. 2017 Oct;40(4):1217-1225. doi: 10.3892/ijmm.2017.3112. Epub 2017 Aug 29.
• [7] AKT-mediated phosphorylation of ATG4B impairs mitochondrial activity and enhances the Warburg effect in hepatocellular carcinoma cells.Autophagy. 2018;14(4):685-701. doi: 10.1080/15548627.2017.1407887. Epub 2018 Jan 29.
• [8] Autophagy maintains tumour growth through circulating arginine.Nature. 2018 Nov;563(7732):569-573. doi: 10.1038/s41586-018-0697-7. Epub 2018 Nov 14.
• [9] Methylation-induced silencing of miR-34a enhances chemoresistance by directly upregulating ATG4B-induced autophagy through AMPK/mTOR pathway in prostate cancer.Oncol Rep. 2016 Jan;35(1):64-72. doi: 10.3892/or.2015.4331. Epub 2015 Oct 16.
• [10] Impaired autophagic activity and ATG4B deficiency are associated with increased endoplasmic reticulum stress-induced lung injury.Aging (Albany NY). 2018 Aug 27;10(8):2098-2112. doi: 10.18632/aging.101532.
• [11] MST4 Phosphorylation of ATG4B Regulates Autophagic Activity, Tumorigenicity, and Radioresistance in Glioblastoma.Cancer Cell. 2017 Dec 11;32(6):840-855.e8. doi: 10.1016/j.ccell.2017.11.005.
• [12] Autophagy related markers (Beclin-1 and ATG4B) are strongly expressed in Wilms' tumor and correlate with favorable histology.Histol Histopathol. 2019 Jan;34(1):47-56. doi: 10.14670/HH-18-023. Epub 2018 Jul 10.
• [13] MIR93 (microRNA -93) regulates tumorigenicity and therapy response of glioblastoma by targeting autophagy.Autophagy. 2019 Jun;15(6):1100-1111. doi: 10.1080/15548627.2019.1569947. Epub 2019 Jan 31.
• [14] Cryptic exon splicing function of TARDBP interacts with autophagy in nervous tissue.Autophagy. 2018;14(8):1398-1403. doi: 10.1080/15548627.2018.1474311. Epub 2018 Jul 28.
• [15] Regulation of ATG4B stability by RNF5 limits basal levels of autophagy and influences susceptibility to bacterial infection.PLoS Genet. 2012;8(10):e1003007. doi: 10.1371/journal.pgen.1003007. Epub 2012 Oct 18.
• [16] Activity-Based Protein Profiling Identifies ATG4B as a Key Host Factor for Enterovirus 71 Proliferation.J Virol. 2019 Nov 26;93(24):e01092-19. doi: 10.1128/JVI.01092-19. Print 2019 Dec 15.
• [17] Autophagy impairment mediated by S-nitrosation of ATG4B leads to neurotoxicity in response to hyperglycemia.Autophagy. 2017 Jul 3;13(7):1145-1160. doi: 10.1080/15548627.2017.1320467.
• [18] SLC27A4 regulate ATG4B activity and control reactions to chemotherapeutics-induced autophagy in human lung cancer cells.Tumour Biol. 2016 May;37(5):6943-52. doi: 10.1007/s13277-015-4587-4. Epub 2015 Dec 11.
• [19] Association of ATG4B and Phosphorylated ATG4B Proteins with Tumorigenesis and Prognosis in Oral Squamous Cell Carcinoma.Cancers (Basel). 2019 Nov 23;11(12):1854. doi: 10.3390/cancers11121854.
• [20] 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.
• [21] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [22] 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.
• [23] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [24] 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.
• [25] Functional gene expression profile underlying methotrexate-induced senescence in human colon cancer cells. Tumour Biol. 2011 Oct;32(5):965-76.
• [26] Inhibition of ATF4-mediated elevation of both autophagy and AKT/mTOR was involved in antitumorigenic activity of curcumin. Food Chem Toxicol. 2023 Mar;173:113609. doi: 10.1016/j.fct.2023.113609. Epub 2023 Jan 12.
• [27] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.