Details of Drug Off-Target (DOT)

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

• DOT Name: Reticulophagy regulator 1 (RETREG1)
• Synonyms: Reticulophagy receptor 1
• Gene Name: RETREG1
• Related Disease:
  Hereditary sensory and autonomic neuropathy type 1
  Hereditary sensory and autonomic neuropathy type 4
  Hereditary sensory and autonomic neuropathy type 5
  Neuropathy, hereditary sensory and autonomic, type 2B
  Adenocarcinoma
  Adenoma
  Advanced cancer
  Allergic rhinitis
  Autonomic neuropathy
  Carcinoma
  Charcot-Marie-Tooth disease type 2
  Colorectal adenoma
  Colorectal carcinoma
  Dengue
  Esophageal cancer
  Hepatocellular carcinoma
  Hereditary sensory and autonomic neuropathy
  Inflammation
  Mental disorder
  Metastatic malignant neoplasm
  Squamous cell carcinoma
  Vascular dementia
  Colon cancer
  Colon carcinoma
  Colorectal adenocarcinoma
  Obesity
  Hereditary sensory and autonomic neuropathy type 2
  Esophageal squamous cell carcinoma
  Cutaneous squamous cell carcinoma
  Ebola virus infection
  Neoplasm
  Nervous system disease
• UniProt ID: RETR1_HUMAN
• PDB ID: 7BRQ; 7FB5
• Sequence:
  MASPAPPEHAEEGCPAPAAEEQAPPSPPPPQASPAERQQQEEEAQEAGAAEGAGLQVEEA
  AGRAAAAVTWLLGEPVLWLGCRADELLSWKRPLRSLLGFVAANLLFWFLALTPWRVYHLI
  SVMILGRVIMQIIKDMVLSRTRGAQLWRSLSESWEVINSKPDERPRLSHCIAESWMNFSI
  FLQEMSLFKQQSPGKFCLLVCSVCTFFTILGSYIPGVILSYLLLLCAFLCPLFKCNDIGQ
  KIYSKIKSVLLKLDFGIGEYINQKKRERSEADKEKSHKDDSELDFSALCPKISLTVAAKE
  LSVSDTDVSEVSWTDNGTFNLSEGYTPQTDTSDDLDRPSEEVFSRDLSDFPSLENGMGTN
  DEDELSLGLPTELKRKKEQLDSGHRPSKETQSAAGLTLPLNSDQTFHLMSNLAGDVITAA
  VTAAIKDQLEGVQQALSQAAPIPEEDTDTEEGDDFELLDQSELDQIESELGLTQDQEAEA
  QQNKKSSGFLSNLLGGH
• Function: Endoplasmic reticulum (ER)-anchored autophagy regulator which mediates ER delivery into lysosomes through sequestration into autophagosomes. Promotes membrane remodeling and ER scission via its membrane bending capacity and targets the fragments into autophagosomes via interaction with ATG8 family proteins. Active under basal conditions. Required for collagen quality control in a LIR motif-dependent manner. Required for long-term survival of nociceptive and autonomic ganglion neurons ; (Microbial infection) During SARS-CoV-2 infection, RETREG1-mediated reticulophagy is promoted by SARS-CoV-2 ORF3A protein. This induces endoplasmic reticulum stress and inflammatory responses and facilitates viral infection.
• Tissue Specificity: Overexpressed in esophageal squamous cell carcinoma .

Molecular Interaction Atlas (MIA) of This DOT

32 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hereditary sensory and autonomic neuropathy type 1	DISLSPO4	Definitive	Biomarker	[1]
Hereditary sensory and autonomic neuropathy type 4	DISNE3R5	Definitive	Biomarker	[1]
Hereditary sensory and autonomic neuropathy type 5	DISFSWS1	Definitive	Biomarker	[1]
Neuropathy, hereditary sensory and autonomic, type 2B	DISYCR9Q	Definitive	Autosomal recessive	[1]
Adenocarcinoma	DIS3IHTY	Strong	Posttranslational Modification	[2]
Adenoma	DIS78ZEV	Strong	Posttranslational Modification	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Allergic rhinitis	DIS3U9HN	Strong	Biomarker	[3]
Autonomic neuropathy	DISI3WJ0	Strong	Genetic Variation	[1]
Carcinoma	DISH9F1N	Strong	Altered Expression	[4]
Charcot-Marie-Tooth disease type 2	DISR30O9	Strong	Biomarker	[1]
Colorectal adenoma	DISTSVHM	Strong	Posttranslational Modification	[2]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[2]
Dengue	DISKH221	Strong	Biomarker	[3]
Esophageal cancer	DISGB2VN	Strong	Altered Expression	[5]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[6]
Hereditary sensory and autonomic neuropathy	DIS2VOAM	Strong	Genetic Variation	[7]
Inflammation	DISJUQ5T	Strong	Biomarker	[8]
Mental disorder	DIS3J5R8	Strong	Genetic Variation	[9]
Metastatic malignant neoplasm	DIS86UK6	Strong	Biomarker	[6]
Squamous cell carcinoma	DISQVIFL	Strong	Altered Expression	[10]
Vascular dementia	DISVO82H	Strong	Biomarker	[11]
Colon cancer	DISVC52G	moderate	Posttranslational Modification	[2]
Colon carcinoma	DISJYKUO	moderate	Posttranslational Modification	[2]
Colorectal adenocarcinoma	DISPQOUB	moderate	Altered Expression	[4]
Obesity	DIS47Y1K	moderate	Altered Expression	[12]
Hereditary sensory and autonomic neuropathy type 2	DIS4TP1G	Supportive	Autosomal recessive	[13]
Esophageal squamous cell carcinoma	DIS5N2GV	Disputed	Biomarker	[14]
Cutaneous squamous cell carcinoma	DIS3LXUG	Limited	Biomarker	[15]
Ebola virus infection	DISJAVM1	Limited	Biomarker	[16]
Neoplasm	DISZKGEW	Limited	Altered Expression	[14]
Nervous system disease	DISJ7GGT	Limited	Genetic Variation	[17]

15 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 Reticulophagy regulator 1 (RETREG1).	[18]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Reticulophagy regulator 1 (RETREG1).	[19]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Reticulophagy regulator 1 (RETREG1).	[20]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Reticulophagy regulator 1 (RETREG1).	[21]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Reticulophagy regulator 1 (RETREG1).	[22]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Reticulophagy regulator 1 (RETREG1).	[23]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Reticulophagy regulator 1 (RETREG1).	[24]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Reticulophagy regulator 1 (RETREG1).	[25]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Reticulophagy regulator 1 (RETREG1).	[26]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Reticulophagy regulator 1 (RETREG1).	[27]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Reticulophagy regulator 1 (RETREG1).	[28]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Reticulophagy regulator 1 (RETREG1).	[29]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Reticulophagy regulator 1 (RETREG1).	[30]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Reticulophagy regulator 1 (RETREG1).	[31]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Reticulophagy regulator 1 (RETREG1).	[32]

References

• [1] Mutations in FAM134B, encoding a newly identified Golgi protein, cause severe sensory and autonomic neuropathy. Nat Genet. 2009 Nov;41(11):1179-81. doi: 10.1038/ng.464. Epub 2009 Oct 18.
• [2] Promoter hypermethylation inactivate tumor suppressor FAM134B and is associated with poor prognosis in colorectal cancer.Genes Chromosomes Cancer. 2018 May;57(5):240-251. doi: 10.1002/gcc.22525. Epub 2018 Jan 30.
• [3] RETREG1 (FAM134B): A new player in human diseases: 15 years after the discovery in cancer.J Cell Physiol. 2018 Jun;233(6):4479-4489. doi: 10.1002/jcp.26384. Epub 2018 Jan 15.
• [4] The roles of JK-1 (FAM134B) expressions in colorectal cancer.Exp Cell Res. 2014 Aug 1;326(1):166-73. doi: 10.1016/j.yexcr.2014.06.013. Epub 2014 Jun 25.
• [5] A PCR-free electrochemical method for messenger RNA detection in cancer tissue samples.Biosens Bioelectron. 2017 Dec 15;98:227-233. doi: 10.1016/j.bios.2017.06.051. Epub 2017 Jun 27.
• [6] FAM134B induces tumorigenesis and epithelial-to-mesenchymal transition via Akt signaling in hepatocellular carcinoma.Mol Oncol. 2019 Apr;13(4):792-810. doi: 10.1002/1878-0261.12429. Epub 2019 Jan 24.
• [7] De novo pathogenic DNM1L variant in a patient diagnosed with atypical hereditary sensory and autonomic neuropathy.Mol Genet Genomic Med. 2019 Oct;7(10):e00961. doi: 10.1002/mgg3.961. Epub 2019 Sep 1.
• [8] Genetic analysis of an allergic rhinitis cohort reveals an intercellular epistasis between FAM134B and CD39.BMC Med Genet. 2014 Jun 27;15:73. doi: 10.1186/1471-2350-15-73.
• [9] Gene-level associations in suicide attempter families show overrepresentation of synaptic genes and genes differentially expressed in brain development.Am J Med Genet B Neuropsychiatr Genet. 2018 Dec;177(8):774-784. doi: 10.1002/ajmg.b.32694. Epub 2018 Oct 31.
• [10] Oncogenic properties of a novel gene JK-1 located in chromosome 5p and its overexpression in human esophageal squamous cell carcinoma.Int J Mol Med. 2007 Jun;19(6):915-23.
• [11] A strong synergistic epistasis between FAM134B and TNFRSF19 on the susceptibility to vascular dementia.Psychiatr Genet. 2011 Feb;21(1):37-41. doi: 10.1097/YPG.0b013e3283413496.
• [12] FAM134B improves preadipocytes differentiation by enhancing mitophagy.Biochim Biophys Acta Mol Cell Biol Lipids. 2019 Dec;1864(12):158508. doi: 10.1016/j.bbalip.2019.08.004. Epub 2019 Aug 22.
• [13] Hereditary Sensory and Autonomic Neuropathy Type II. 2010 Nov 23 [updated 2021 Apr 1]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [14] FAM134B promotes esophageal squamous cell carcinoma in vitro and its correlations with clinicopathologic features.Hum Pathol. 2019 May;87:1-10. doi: 10.1016/j.humpath.2018.11.033. Epub 2019 Feb 20.
• [15] MicroRNA-186 promotes cell proliferation and inhibits cell apoptosis in cutaneous squamous cell carcinoma by targeting RETREG1.Exp Ther Med. 2019 Mar;17(3):1930-1938. doi: 10.3892/etm.2019.7154. Epub 2019 Jan 7.
• [16] FAM134B, the Selective Autophagy Receptor for Endoplasmic Reticulum Turnover, Inhibits Replication of Ebola Virus Strains Makona and Mayinga.J Infect Dis. 2016 Oct 15;214(suppl 3):S319-S325. doi: 10.1093/infdis/jiw270. Epub 2016 Aug 10.
• [17] Identification of Novel FAM134B (JK1) Mutations in Oesophageal Squamous Cell Carcinoma.Sci Rep. 2016 Jul 4;6:29173. doi: 10.1038/srep29173.
• [18] The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):124-34.
• [19] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [20] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [21] 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.
• [22] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [23] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [24] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [25] 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.
• [26] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [27] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [28] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [29] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [30] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [31] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [32] 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.