Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTRGX0OV)

• DOT Name: Calcium-binding and coiled-coil domain-containing protein 2 (CALCOCO2)
• Synonyms: Antigen nuclear dot 52 kDa protein; Nuclear domain 10 protein NDP52; Nuclear domain 10 protein 52; Nuclear dot protein 52
• Gene Name: CALCOCO2
• Related Disease:
  Colorectal carcinoma
  Colorectal neoplasm
  Alcoholic cirrhosis of liver
  Alzheimer disease
  Amyloidosis
  Bacillary dysentery
  Cardiac failure
  Congestive heart failure
  Crohn disease
  Influenza
  Liver cirrhosis
  Non-insulin dependent diabetes
  Parkinson disease
  Amyotrophic lateral sclerosis
  Frontotemporal dementia
• UniProt ID: CACO2_HUMAN
• PDB ID: 2MXP; 3VVV; 3VVW; 4GXL; 4HAN; 4XKL; 5AAQ; 5Z7A; 5Z7L; 7EAA
• Pfam ID: PF17751
• Sequence:
  MEETIKDPPTSAVLLDHCHFSQVIFNSVEKFYIPGGDVTCHYTFTQHFIPRRKDWIGIFR
  VGWKTTREYYTFMWVTLPIDLNNKSAKQQEVQFKAYYLPKDDEYYQFCYVDEDGVVRGAS
  IPFQFRPENEEDILVVTTQGEVEEIEQHNKELCKENQELKDSCISLQKQNSDMQAELQKK
  QEELETLQSINKKLELKVKEQKDYWETELLQLKEQNQKMSSENEKMGIRVDQLQAQLSTQ
  EKEMEKLVQGDQDKTEQLEQLKKENDHLFLSLTEQRKDQKKLEQTVEQMKQNETTAMKKQ
  QELMDENFDLSKRLSENEIICNALQRQKERLEGENDLLKRENSRLLSYMGLDFNSLPYQV
  PTSDEGGARQNPGLAYGNPYSGIQESSSPSPLSIKKCPICKADDICDHTLEQQQMQPLCF
  NCPICDKIFPATEKQIFEDHVFCHSL
• Function: Xenophagy-specific receptor required for autophagy-mediated intracellular bacteria degradation. Acts as an effector protein of galectin-sensed membrane damage that restricts the proliferation of infecting pathogens such as Salmonella typhimurium upon entry into the cytosol by targeting LGALS8-associated bacteria for autophagy. Initially orchestrates bacteria targeting to autophagosomes and subsequently ensures pathogen degradation by regulating pathogen-containing autophagosome maturation. Bacteria targeting to autophagosomes relies on its interaction with MAP1LC3A, MAP1LC3B and/or GABARAPL2, whereas regulation of pathogen-containing autophagosome maturation requires the interaction with MAP3LC3C. May play a role in ruffle formation and actin cytoskeleton organization and seems to negatively regulate constitutive secretion.
• Tissue Specificity: Expressed in all tissues tested with highest expression in skeletal muscle and lowest in brain.
• KEGG Pathway:
  Mitophagy - animal (hsa04137)
  Autophagy - animal (hsa04140)
  Shigellosis (hsa05131)
  Influenza A (hsa05164)

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Colorectal carcinoma	DIS5PYL0	Definitive	Biomarker	[1]
Colorectal neoplasm	DISR1UCN	Definitive	Biomarker	[1]
Alcoholic cirrhosis of liver	DISQ1WRT	Strong	Genetic Variation	[2]
Alzheimer disease	DISF8S70	Strong	Biomarker	[3]
Amyloidosis	DISHTAI2	Strong	Biomarker	[4]
Bacillary dysentery	DISFZHKN	Strong	Biomarker	[5]
Cardiac failure	DISDC067	Strong	Biomarker	[6]
Congestive heart failure	DIS32MEA	Strong	Biomarker	[6]
Crohn disease	DIS2C5Q8	Strong	Genetic Variation	[7]
Influenza	DIS3PNU3	Strong	Biomarker	[8]
Liver cirrhosis	DIS4G1GX	Strong	Genetic Variation	[2]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Genetic Variation	[9]
Parkinson disease	DISQVHKL	Strong	Biomarker	[10]
Amyotrophic lateral sclerosis	DISF7HVM	Disputed	Biomarker	[11]
Frontotemporal dementia	DISKYHXL	Disputed	Biomarker	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Calcium-binding and coiled-coil domain-containing protein 2 (CALCOCO2).	[12]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Calcium-binding and coiled-coil domain-containing protein 2 (CALCOCO2).	[18]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Calcium-binding and coiled-coil domain-containing protein 2 (CALCOCO2).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Calcium-binding and coiled-coil domain-containing protein 2 (CALCOCO2).	[13]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Calcium-binding and coiled-coil domain-containing protein 2 (CALCOCO2).	[14]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Calcium-binding and coiled-coil domain-containing protein 2 (CALCOCO2).	[15]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Calcium-binding and coiled-coil domain-containing protein 2 (CALCOCO2).	[16]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Calcium-binding and coiled-coil domain-containing protein 2 (CALCOCO2).	[17]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Calcium-binding and coiled-coil domain-containing protein 2 (CALCOCO2).	[19]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Calcium-binding and coiled-coil domain-containing protein 2 (CALCOCO2).	[21]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Calcium-binding and coiled-coil domain-containing protein 2 (CALCOCO2).	[22]
GALLICACID	DM6Y3A0	Investigative	GALLICACID increases the expression of Calcium-binding and coiled-coil domain-containing protein 2 (CALCOCO2).	[23]
Manganese	DMKT129	Investigative	Manganese increases the expression of Calcium-binding and coiled-coil domain-containing protein 2 (CALCOCO2).	[24]

References

• [1] Highly Expressed Genes in Rapidly Proliferating Tumor Cells as New Targets for Colorectal Cancer Treatment.Clin Cancer Res. 2015 Aug 15;21(16):3695-704. doi: 10.1158/1078-0432.CCR-14-2457. Epub 2015 May 5.
• [2] A variant in the nuclear dot protein 52kDa gene increases the risk for spontaneous bacterial peritonitis in patients with alcoholic liver cirrhosis.Dig Liver Dis. 2016 Jan;48(1):62-8. doi: 10.1016/j.dld.2015.09.011. Epub 2015 Sep 28.
• [3] Nrf2 reduces levels of phosphorylated tau protein by inducing autophagy adaptor protein NDP52.Nat Commun. 2014 Mar 25;5:3496. doi: 10.1038/ncomms4496.
• [4] PINK1 signalling rescues amyloid pathology and mitochondrial dysfunction in Alzheimer's disease.Brain. 2017 Dec 1;140(12):3233-3251. doi: 10.1093/brain/awx258.
• [5] p62 and NDP52 proteins target intracytosolic Shigella and Listeria to different autophagy pathways.J Biol Chem. 2011 Jul 29;286(30):26987-95. doi: 10.1074/jbc.M111.223610. Epub 2011 Jun 6.
• [6] The altered expression of autophagy-related genes participates in heart failure: NRBP2 and CALCOCO2 are associated with left ventricular dysfunction parameters in human dilated cardiomyopathy.PLoS One. 2019 Apr 22;14(4):e0215818. doi: 10.1371/journal.pone.0215818. eCollection 2019.
• [7] Association between variants of PRDM1 and NDP52 and Crohn's disease, based on exome sequencing and functional studies.Gastroenterology. 2013 Aug;145(2):339-47. doi: 10.1053/j.gastro.2013.04.040. Epub 2013 Apr 25.
• [8] Influenza virus protein PB1-F2 interacts with CALCOCO2 (NDP52) to modulate innate immune response.J Gen Virol. 2017 Jun;98(6):1196-1208. doi: 10.1099/jgv.0.000782. Epub 2017 Jun 14.
• [9] Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes.Nat Genet. 2018 Apr;50(4):559-571. doi: 10.1038/s41588-018-0084-1. Epub 2018 Apr 9.
• [10] LRRK2 mutations impair depolarization-induced mitophagy through inhibition of mitochondrial accumulation of RAB10.Autophagy. 2020 Feb;16(2):203-222. doi: 10.1080/15548627.2019.1603548. Epub 2019 Apr 19.
• [11] The cargo receptor SQSTM1 ameliorates neurofibrillary tangle pathology and spreading through selective targeting of pathological MAPT (microtubule associated protein tau).Autophagy. 2019 Apr;15(4):583-598. doi: 10.1080/15548627.2018.1532258. Epub 2018 Oct 16.
• [12] 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.
• [13] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [14] 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.
• [15] 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.
• [16] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [17] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [18] 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.
• [19] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [20] 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.
• [21] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [22] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [23] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.
• [24] Gene expression profiling of human primary astrocytes exposed to manganese chloride indicates selective effects on several functions of the cells. Neurotoxicology. 2007 May;28(3):478-89.