Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTD9HN3X)

• DOT Name: Cysteine protease ATG4C (ATG4C)
• Synonyms: EC 3.4.22.-; AUT-like 3 cysteine endopeptidase; Autophagy-related cysteine endopeptidase 3; Autophagin-3; Autophagy-related protein 4 homolog C; HsAPG4C
• Gene Name: ATG4C
• Related Disease:
  Tuberculosis
  Advanced cancer
  Alzheimer disease
  Breast cancer
  Breast carcinoma
  Glioma
• UniProt ID: ATG4C_HUMAN
• EC Number: 3.4.22.-
• Pfam ID: PF20166 ; PF03416
• Sequence:
  MEATGTDEVDKLKTKFISAWNNMKYSWVLKTKTYFSRNSPVLLLGKCYHFKYEDEDKTLP
  AESGCTIEDHVIAGNVEEFRKDFISRIWLTYREEFPQIEGSALTTDCGWGCTLRTGQMLL
  AQGLILHFLGRAWTWPDALNIENSDSESWTSHTVKKFTASFEASLSGEREFKTPTISLKE
  TIGKYSDDHEMRNEVYHRKIISWFGDSPLALFGLHQLIEYGKKSGKKAGDWYGPAVVAHI
  LRKAVEEARHPDLQGITIYVAQDCTVYNSDVIDKQSASMTSDNADDKAVIILVPVRLGGE
  RTNTDYLEFVKGILSLEYCVGIIGGKPKQSYYFAGFQDDSLIYMDPHYCQSFVDVSIKDF
  PLETFHCPSPKKMSFRKMDPSCTIGFYCRNVQDFKRASEEITKMLKFSSKEKYPLFTFVN
  GHSRDYDFTSTTTNEEDLFSEDEKKQLKRFSTEEFVLL
• Function: 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. Compared to ATG4B, the major protein for proteolytic activation of ATG8 proteins, shows weaker ability to cleave the C-terminal amino acid of ATG8 proteins, while it displays stronger delipidation activity. In contrast to other members of the family, weakly or not involved in phagophore growth during mitophagy.
• KEGG Pathway:
  Autophagy - other (hsa04136)
  Autophagy - animal (hsa04140)
• Reactome Pathway: Macroautophagy (R-HSA-1632852)

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Tuberculosis	DIS2YIMD	Definitive	Genetic Variation	[1]
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[2]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[2]
Breast cancer	DIS7DPX1	Strong	Biomarker	[3]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[3]
Glioma	DIS5RPEH	Strong	Biomarker	[4]

3 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 Cysteine protease ATG4C (ATG4C).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Cysteine protease ATG4C (ATG4C).	[6]
Clorgyline	DMCEUJD	Approved	Clorgyline increases the expression of Cysteine protease ATG4C (ATG4C).	[7]

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 ATG4C (ATG4C).	[8]

References

• [1] Investigating the Role of Gene-Gene Interactions in TB Susceptibility.PLoS One. 2015 Apr 28;10(4):e0123970. doi: 10.1371/journal.pone.0123970. eCollection 2014.
• [2] A genome-wide association study of aging.Neurobiol Aging. 2011 Nov;32(11):2109.e15-28. doi: 10.1016/j.neurobiolaging.2011.05.026. Epub 2011 Jul 22.
• [3] ATM kinase sustains breast cancer stem-like cells by promoting ATG4C expression and autophagy.Oncotarget. 2017 Mar 28;8(13):21692-21709. doi: 10.18632/oncotarget.15537.
• [4] Knockdown ATG4C inhibits gliomas progression and promotes temozolomide chemosensitivity by suppressing autophagic flux.J Exp Clin Cancer Res. 2019 Jul 10;38(1):298. doi: 10.1186/s13046-019-1287-8.
• [5] 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.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] Anti-oncogenic and pro-differentiation effects of clorgyline, a monoamine oxidase A inhibitor, on high grade prostate cancer cells. BMC Med Genomics. 2009 Aug 20;2:55. doi: 10.1186/1755-8794-2-55.
• [8] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.