Details of Drug Off-Target (DOT)

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

• DOT Name: Erlin-1 (ERLIN1)
• Synonyms: Endoplasmic reticulum lipid raft-associated protein 1; Protein KE04; Stomatin-prohibitin-flotillin-HflC/K domain-containing protein 1; SPFH domain-containing protein 1
• Gene Name: ERLIN1
• Related Disease:
  Cerebellar ataxia
  Fatty liver disease
  Hepatitis C virus infection
  Hereditary spastic paraplegia
  Hereditary spastic paraplegia 62
  Non-alcoholic fatty liver disease
  Schizophrenia
  Coronary atherosclerosis
  Coronary heart disease
  Amyotrophic lateral sclerosis
  Subarachnoid hemorrhage
• UniProt ID: ERLN1_HUMAN
• Pfam ID: PF01145
• Sequence:
  MNMTQARVLVAAVVGLVAVLLYASIHKIEEGHLAVYYRGGALLTSPSGPGYHIMLPFITT
  FRSVQTTLQTDEVKNVPCGTSGGVMIYIDRIEVVNMLAPYAVFDIVRNYTADYDKTLIFN
  KIHHELNQFCSAHTLQEVYIELFDQIDENLKQALQKDLNLMAPGLTIQAVRVTKPKIPEA
  IRRNFELMEAEKTKLLIAAQKQKVVEKEAETERKKAVIEAEKIAQVAKIRFQQKVMEKET
  EKRISEIEDAAFLAREKAKADAEYYAAHKYATSNKHKLTPEYLELKKYQAIASNSKIYFG
  SNIPNMFVDSSCALKYSDIRTGRESSLPSKEALEPSGENVIQNKESTG
• Function: Component of the ERLIN1/ERLIN2 complex which mediates the endoplasmic reticulum-associated degradation (ERAD) of inositol 1,4,5-trisphosphate receptors (IP3Rs). Involved in regulation of cellular cholesterol homeostasis by regulation the SREBP signaling pathway. Binds cholesterol and may promote ER retention of the SCAP-SREBF complex ; (Microbial infection) Required early in hepatitis C virus (HCV) infection to initiate RNA replication, and later in the infection to support infectious virus production.
• Tissue Specificity: Expressed in heart, placenta, liver, kidney, pancreas, prostate, testis, ovary and small intestine.
• Reactome Pathway:
  Defective CFTR causes cystic fibrosis (R-HSA-5678895)
  ABC-family proteins mediated transport (R-HSA-382556)

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cerebellar ataxia	DIS9IRAV	Strong	Genetic Variation	[1]
Fatty liver disease	DIS485QZ	Strong	Genetic Variation	[2]
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[3]
Hereditary spastic paraplegia	DISGZQV1	Strong	Genetic Variation	[1]
Hereditary spastic paraplegia 62	DISM2A1M	Strong	Autosomal recessive	[4]
Non-alcoholic fatty liver disease	DISDG1NL	Strong	Genetic Variation	[2]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[5]
Coronary atherosclerosis	DISKNDYU	Disputed	Genetic Variation	[6]
Coronary heart disease	DIS5OIP1	Disputed	Genetic Variation	[6]
Amyotrophic lateral sclerosis	DISF7HVM	Limited	Autosomal recessive	[7]
Subarachnoid hemorrhage	DISI7I8Y	Limited	Genetic Variation	[8]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Chlorothiazide	DMLHESP	Approved	Erlin-1 (ERLIN1) increases the Metabolic disorder ADR of Chlorothiazide.	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Erlin-1 (ERLIN1).	[9]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Erlin-1 (ERLIN1).	[10]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Erlin-1 (ERLIN1).	[11]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Erlin-1 (ERLIN1).	[12]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Erlin-1 (ERLIN1).	[13]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Erlin-1 (ERLIN1).	[14]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol decreases the expression of Erlin-1 (ERLIN1).	[15]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Erlin-1 (ERLIN1).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Erlin-1 (ERLIN1).	[18]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Erlin-1 (ERLIN1).	[19]

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 decreases the methylation of Erlin-1 (ERLIN1).	[17]

References

• [1] Bi-allelic variants in RNF170 are associated with hereditary spastic paraplegia.Nat Commun. 2019 Oct 21;10(1):4790. doi: 10.1038/s41467-019-12620-9.
• [2] The ERLIN1-CHUK-CWF19L1 gene cluster influences liver fat deposition and hepatic inflammation in the NHLBI Family Heart Study.Atherosclerosis. 2013 May;228(1):175-80. doi: 10.1016/j.atherosclerosis.2013.01.038. Epub 2013 Feb 18.
• [3] The Host Factor Erlin-1 is Required for Efficient Hepatitis C Virus Infection.Cells. 2019 Dec 2;8(12):1555. doi: 10.3390/cells8121555.
• [4] Exome sequencing links corticospinal motor neuron disease to common neurodegenerative disorders. Science. 2014 Jan 31;343(6170):506-511. doi: 10.1126/science.1247363.
• [5] Pleiotropic Meta-Analysis of Cognition, Education, and Schizophrenia Differentiates Roles of Early Neurodevelopmental and Adult Synaptic Pathways.Am J Hum Genet. 2019 Aug 1;105(2):334-350. doi: 10.1016/j.ajhg.2019.06.012.
• [6] Genomic structural variations for cardiovascular and metabolic comorbidity.Sci Rep. 2017 Jan 25;7:41268. doi: 10.1038/srep41268.
• [7] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [8] Association of genetic variants with hemorrhagic stroke in Japanese individuals.Int J Mol Med. 2010 Apr;25(4):649-56. doi: 10.3892/ijmm_00000388.
• [9] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [10] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [11] 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.
• [12] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [13] 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.
• [14] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [15] Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
• [16] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [17] 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.
• [18] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [19] 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.
• [20] Genome-wide association analyses suggest NELL1 influences adverse metabolic response to HCTZ in African Americans. Pharmacogenomics J. 2014 Feb;14(1):35-40. doi: 10.1038/tpj.2013.3. Epub 2013 Feb 12.