Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTSWUO4R)

• DOT Name: Cysteine protease ATG4D (ATG4D)
• Synonyms: EC 3.4.22.-; AUT-like 4 cysteine endopeptidase; Autophagy-related cysteine endopeptidase 4; Autophagin-4; Autophagy-related protein 4 homolog D; HsAPG4D
• Gene Name: ATG4D
• Related Disease:
  Glioma
  Matthew-Wood syndrome
  Neoplasm
  Breast cancer
  Breast carcinoma
  Lung cancer
  Lung squamous cell carcinoma
  Complex neurodevelopmental disorder
• UniProt ID: ATG4D_HUMAN
• EC Number: 3.4.22.-
• Pfam ID: PF03416
• Sequence:
  MNSVSPAAAQYRSSSPEDARRRPEARRPRGPRGPDPNGLGPSGASGPALGSPGAGPSEPD
  EVDKFKAKFLTAWNNVKYGWVVKSRTSFSKISSIHLCGRRYRFEGEGDIQRFQRDFVSRL
  WLTYRRDFPPLPGGCLTSDCGWGCMLRSGQMMLAQGLLLHFLPRDWTWAEGMGLGPPELS
  GSASPSRYHGPARWMPPRWAQGAPELEQERRHRQIVSWFADHPRAPFGLHRLVELGQSSG
  KKAGDWYGPSLVAHILRKAVESCSDVTRLVVYVSQDCTVYKADVARLVARPDPTAEWKSV
  VILVPVRLGGETLNPVYVPCVKELLRCELCLGIMGGKPRHSLYFIGYQDDFLLYLDPHYC
  QPTVDVSQADFPLESFHCTSPRKMAFAKMDPSCTVGFYAGDRKEFETLCSELTRVLSSSS
  ATERYPMFTLAEGHAQDHSLDDLCSQLAQPTLRLPRTGRLLRAKRPSSEDFVFL
• Function: [Cysteine protease ATG4D]: Cysteine protease that plays a key role in autophagy by mediating both proteolytic activation and delipidation of ATG8 family proteins. The protease activity is required for proteolytic activation of ATG8 family proteins: cleaves the C-terminal amino acid of ATG8 proteins MAP1LC3 and GABARAPL2, 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. 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). ATG4D plays a role in the autophagy-mediated neuronal homeostasis in the central nervous system. Compared to other members of the family (ATG4A, ATG4B or ATG4C), constitutes the major protein for the delipidation activity, while it promotes weak proteolytic activation of ATG8 proteins. 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 ; [Cysteine protease ATG4D, mitochondrial]: Plays a role as an autophagy regulator that links mitochondrial dysfunction with apoptosis. The mitochondrial import of ATG4D during cellular stress and differentiation may play important roles in the regulation of mitochondrial physiology, ROS, mitophagy and cell viability.
• Tissue Specificity: Widely expressed in testis.
• KEGG Pathway:
  Autophagy - other (hsa04136)
  Autophagy - animal (hsa04140)
• Reactome Pathway: Macroautophagy (R-HSA-1632852)

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Glioma	DIS5RPEH	Strong	Altered Expression	[1]
Matthew-Wood syndrome	DISA7HR7	Strong	Biomarker	[2]
Neoplasm	DISZKGEW	Strong	Biomarker	[3]
Breast cancer	DIS7DPX1	Disputed	Altered Expression	[4]
Breast carcinoma	DIS2UE88	Disputed	Altered Expression	[4]
Lung cancer	DISCM4YA	Disputed	Altered Expression	[4]
Lung squamous cell carcinoma	DISXPIBD	Disputed	Altered Expression	[4]
Complex neurodevelopmental disorder	DISB9AFI	Limited	Autosomal recessive	[5]

3 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 Cysteine protease ATG4D (ATG4D).	[6]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Cysteine protease ATG4D (ATG4D).	[7]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Cysteine protease ATG4D (ATG4D).	[8]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Cysteine protease ATG4D (ATG4D).	[9]

References

• [1] Malat1 activates autophagy and promotes cell proliferation by sponging miR-101 and upregulating STMN1, RAB5A and ATG4D expression in glioma.Biochem Biophys Res Commun. 2017 Oct 21;492(3):480-486. doi: 10.1016/j.bbrc.2017.08.070. Epub 2017 Aug 20.
• [2] SNHG14 enhances gemcitabine resistance by sponging miR-101 to stimulate cell autophagy in pancreatic cancer.Biochem Biophys Res Commun. 2019 Mar 19;510(4):508-514. doi: 10.1016/j.bbrc.2019.01.109. Epub 2019 Feb 5.
• [3] The Influence of Tumor Microenvironment on ATG4D Gene Expression in Colorectal Cancer Patients.Med Oncol. 2018 Oct 29;35(12):159. doi: 10.1007/s12032-018-1220-6.
• [4] Cross-cancer profiling of molecular alterations within the human autophagy interaction network.Autophagy. 2015;11(9):1668-87. doi: 10.1080/15548627.2015.1067362.
• [5] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [6] Low Autophagy (ATG) Gene Expression Is Associated with an Immature AML Blast Cell Phenotype and Can Be Restored during AML Differentiation Therapy. Oxid Med Cell Longev. 2018 Mar 18;2018:1482795. doi: 10.1155/2018/1482795. eCollection 2018.
• [7] 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.
• [8] Functional gene expression profile underlying methotrexate-induced senescence in human colon cancer cells. Tumour Biol. 2011 Oct;32(5):965-76.
• [9] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.