Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTOOXC7B)

• DOT Name: RanBP-type and C3HC4-type zinc finger-containing protein 1 (RBCK1)
• Synonyms: EC 2.3.2.31; HBV-associated factor 4; Heme-oxidized IRP2 ubiquitin ligase 1; HOIL-1; Hepatitis B virus X-associated protein 4; RING finger protein 54; RING-type E3 ubiquitin transferase HOIL-1; Ubiquitin-conjugating enzyme 7-interacting protein 3
• Gene Name: RBCK1
• Related Disease:
  Polyglucosan body myopathy 1 with or without immunodeficiency
  Autoinflammatory syndrome with pyogenic bacterial infection and amylopectinosis
  Obsolete polyglucosan body myopathy type 1
• UniProt ID: HOIL1_HUMAN
• PDB ID: 2CRC; 2LGY; 4DBG; 7V8E; 7YUI; 7YUJ; 8BVL; 8EAZ
• EC Number: 2.3.2.31
• Pfam ID: PF13445
• Sequence:
  MDEKTKKAEEMALSLTRAVAGGDEQVAMKCAIWLAEQRVPLSVQLKPEVSPTQDIRLWVS
  VEDAQMHTVTIWLTVRPDMTVASLKDMVFLDYGFPPVLQQWVIGQRLARDQETLHSHGVR
  QNGDSAYLYLLSARNTSLNPQELQRERQLRMLEDLGFKDLTLQPRGPLEPGPPKPGVPQE
  PGRGQPDAVPEPPPVGWQCPGCTFINKPTRPGCEMCCRARPEAYQVPASYQPDEEERARL
  AGEEEALRQYQQRKQQQQEGNYLQHVQLDQRSLVLNTEPAECPVCYSVLAPGEAVVLREC
  LHTFCRECLQGTIRNSQEAEVSCPFIDNTYSCSGKLLEREIKALLTPEDYQRFLDLGISI
  AENRSAFSYHCKTPDCKGWCFFEDDVNEFTCPVCFHVNCLLCKAIHEQMNCKEYQEDLAL
  RAQNDVAARQTTEMLKVMLQQGEAMRCPQCQIVVQKKDGCDWIRCTVCHTEICWVTKGPR
  WGPGGPGDTSGGCRCRVNGIPCHPSCQNCH
• Function: E3 ubiquitin-protein ligase, which accepts ubiquitin from specific E2 ubiquitin-conjugating enzymes, such as UBE2L3/UBCM4, and then transfers it to substrates. Functions as an E3 ligase for oxidized IREB2 and both heme and oxygen are necessary for IREB2 ubiquitination. Promotes ubiquitination of TAB2 and IRF3 and their degradation by the proteasome. Component of the LUBAC complex which conjugates linear ('Met-1'-linked) polyubiquitin chains to substrates and plays a key role in NF-kappa-B activation and regulation of inflammation. LUBAC conjugates linear polyubiquitin to IKBKG and RIPK1 and is involved in activation of the canonical NF-kappa-B and the JNK signaling pathways. Linear ubiquitination mediated by the LUBAC complex interferes with TNF-induced cell death and thereby prevents inflammation. LUBAC is recruited to the TNF-R1 signaling complex (TNF-RSC) following polyubiquitination of TNF-RSC components by BIRC2 and/or BIRC3 and to conjugate linear polyubiquitin to IKBKG and possibly other components contributing to the stability of the complex. The LUBAC complex is also involved in innate immunity by conjugating linear polyubiquitin chains at the surface of bacteria invading the cytosol to form the ubiquitin coat surrounding bacteria. LUBAC is not able to initiate formation of the bacterial ubiquitin coat, and can only promote formation of linear polyubiquitins on pre-existing ubiquitin. The bacterial ubiquitin coat acts as an 'eat-me' signal for xenophagy and promotes NF-kappa-B activation. Together with OTULIN, the LUBAC complex regulates the canonical Wnt signaling during angiogenesis. Binds polyubiquitin of different linkage types.
• KEGG Pathway:
  Necroptosis (hsa04217)
  NOD-like receptor sig.ling pathway (hsa04621)
  Shigellosis (hsa05131)
• Reactome Pathway:
  Regulation of TNFR1 signaling (R-HSA-5357905)
  TNFR1-induced NF-kappa-B signaling pathway (R-HSA-5357956)
  Antigen processing (R-HSA-983168)
  TNFR1-induced proapoptotic signaling (R-HSA-5357786)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Polyglucosan body myopathy 1 with or without immunodeficiency	DISKOIME	Strong	Autosomal recessive	[1]
Autoinflammatory syndrome with pyogenic bacterial infection and amylopectinosis	DISJ79IN	Supportive	Autosomal recessive	[2]
Obsolete polyglucosan body myopathy type 1	DISAWE6V	Supportive	Autosomal recessive	[3]

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 RanBP-type and C3HC4-type zinc finger-containing protein 1 (RBCK1).	[4]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of RanBP-type and C3HC4-type zinc finger-containing protein 1 (RBCK1).	[15]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of RanBP-type and C3HC4-type zinc finger-containing protein 1 (RBCK1).	[17]

12 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 RanBP-type and C3HC4-type zinc finger-containing protein 1 (RBCK1).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of RanBP-type and C3HC4-type zinc finger-containing protein 1 (RBCK1).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of RanBP-type and C3HC4-type zinc finger-containing protein 1 (RBCK1).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of RanBP-type and C3HC4-type zinc finger-containing protein 1 (RBCK1).	[8]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of RanBP-type and C3HC4-type zinc finger-containing protein 1 (RBCK1).	[9]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of RanBP-type and C3HC4-type zinc finger-containing protein 1 (RBCK1).	[10]
Selenium	DM25CGV	Approved	Selenium increases the expression of RanBP-type and C3HC4-type zinc finger-containing protein 1 (RBCK1).	[11]
Dexamethasone	DMMWZET	Approved	Dexamethasone decreases the expression of RanBP-type and C3HC4-type zinc finger-containing protein 1 (RBCK1).	[12]
Hydroquinone	DM6AVR4	Approved	Hydroquinone increases the expression of RanBP-type and C3HC4-type zinc finger-containing protein 1 (RBCK1).	[13]
Ethanol	DMDRQZU	Approved	Ethanol increases the expression of RanBP-type and C3HC4-type zinc finger-containing protein 1 (RBCK1).	[14]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of RanBP-type and C3HC4-type zinc finger-containing protein 1 (RBCK1).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of RanBP-type and C3HC4-type zinc finger-containing protein 1 (RBCK1).	[18]

References

• [1] LUBAC, a novel ubiquitin ligase for linear ubiquitination, is crucial for inflammation and immune responses. Microbes Infect. 2012 Jul;14(7-8):563-72. doi: 10.1016/j.micinf.2012.01.011. Epub 2012 Jan 25.
• [2] Immunodeficiency, autoinflammation and amylopectinosis in humans with inherited HOIL-1 and LUBAC deficiency. Nat Immunol. 2012 Dec;13(12):1178-86. doi: 10.1038/ni.2457. Epub 2012 Oct 28.
• [3] Polyglucosan body myopathy caused by defective ubiquitin ligase RBCK1. Ann Neurol. 2013 Dec;74(6):914-9. doi: 10.1002/ana.23963.
• [4] 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.
• [5] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [6] 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.
• [7] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [8] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [9] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [10] 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.
• [11] 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.
• [12] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [13] Keratinocyte-derived IL-36gama plays a role in hydroquinone-induced chemical leukoderma through inhibition of melanogenesis in human epidermal melanocytes. Arch Toxicol. 2019 Aug;93(8):2307-2320.
• [14] Gene expression signatures after ethanol exposure in differentiating embryoid bodies. Toxicol In Vitro. 2018 Feb;46:66-76.
• [15] 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.
• [16] 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.
• [17] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [18] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.