Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTF1UIZC)

• DOT Name: Run domain Beclin-1-interacting and cysteine-rich domain-containing protein (RUBCN)
• Synonyms: Rubicon; Beclin-1 associated RUN domain containing protein; Baron
• Gene Name: RUBCN
• Related Disease:
  Cerebellar ataxia
  Hepatitis B virus infection
  Systemic lupus erythematosus
  Autosomal recessive spinocerebellar ataxia 15
• UniProt ID: RUBIC_HUMAN
• PDB ID: 6WCW
• Pfam ID: PF13901 ; PF21054 ; PF02759
• Sequence:
  MRPEGAGMELGGGEERLPEESRREHWQLLGNLKTTVEGLVSTNSPNVWSKYGGLERLCRD
  MQSILYHGLIRDQACRRQTDYWQFVKDIRWLSPHSALHVEKFISVHENDQSSADGASERA
  VAELWLQHSLQYHCLSAQLRPLLGDRQYIRKFYTDAAFLLSDAHVTAMLQCLEAVEQNNP
  RLLAQIDASMFARKHESPLLVTKSQSLTALPSSTYTPPNSYAQHSYFGSFSSLHQSVPNN
  GSERRSTSFPLSGPPRKPQESRGHVSPAEDQTIQAPPVSVSALARDSPLTPNEMSSSTLT
  SPIEASWVSSQNDSPGDASEGPEYLAIGNLDPRGRTASCQSHSSNAESSSSNLFSSSSSQ
  KPDSAASSLGDQEGGGESQLSSVLRRSSFSEGQTLTVTSGAKKSHIRSHSDTSIASRGAP
  ESCNDKAKLRGPLPYSGQSSEVSTPSSLYMEYEGGRYLCSGEGMFRRPSEGQSLISYLSE
  QDFGSCADLEKENAHFSISESLIAAIELMKCNMMSQCLEEEEVEEEDSDREIQELKQKIR
  LRRQQIRTKNLLPMYQEAEHGSFRVTSSSSQFSSRDSAQLSDSGSADEVDEFEIQDADIR
  RNTASSSKSFVSSQSFSHCFLHSTSAEAVAMGLLKQFEGMQLPAASELEWLVPEHDAPQK
  LLPIPDSLPISPDDGQHADIYKLRIRVRGNLEWAPPRPQIIFNVHPAPTRKIAVAKQNYR
  CAGCGIRTDPDYIKRLRYCEYLGKYFCQCCHENAQMAIPSRVLRKWDFSKYYVSNFSKDL
  LIKIWNDPLFNVQDINSALYRKVKLLNQVRLLRVQLCHMKNMFKTCRLAKELLDSFDTVP
  GHLTEDLHLYSLNDLTATRKGELGPRLAELTRAGATHVERCMLCQAKGFICEFCQNEDDI
  IFPFELHKCRTCEECKACYHKACFKSGSCPRCERLQARREALARQSLESYLSDYEEEPAE
  ALALEAAVLEAT
• Function: Inhibits PIK3C3 activity; under basal conditions negatively regulates PI3K complex II (PI3KC3-C2) function in autophagy. Negatively regulates endosome maturation and degradative endocytic trafficking and impairs autophagosome maturation process. Can sequester UVRAG from association with a class C Vps complex (possibly the HOPS complex) and negatively regulates Rab7 activation ; Involved in regulation of pathogen-specific host defense of activated macrophages. Following bacterial infection promotes NADH oxidase activity by association with CYBA thereby affecting TLR2 signaling and probably other TLR-NOX pathways. Stabilizes the CYBA:CYBB NADPH oxidase heterodimer, increases its association with TLR2 and its phagosome trafficking to induce antimicrobial burst of ROS and production of inflammatory cytokines. Following fungal or viral infection (implicating CLEC7A (dectin-1)-mediated myeloid cell activation or RIGI-dependent sensing of RNA viruses) negatively regulates pro-inflammatory cytokine production by association with CARD9 and sequestering it from signaling complexes.
• KEGG Pathway: Autophagy - animal (hsa04140)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cerebellar ataxia	DIS9IRAV	Strong	Biomarker	[1]
Hepatitis B virus infection	DISLQ2XY	Strong	Altered Expression	[2]
Systemic lupus erythematosus	DISI1SZ7	Strong	Biomarker	[3]
Autosomal recessive spinocerebellar ataxia 15	DISAUTC6	Supportive	Autosomal recessive	[4]

9 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 Run domain Beclin-1-interacting and cysteine-rich domain-containing protein (RUBCN).	[5]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Run domain Beclin-1-interacting and cysteine-rich domain-containing protein (RUBCN).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Run domain Beclin-1-interacting and cysteine-rich domain-containing protein (RUBCN).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Run domain Beclin-1-interacting and cysteine-rich domain-containing protein (RUBCN).	[8]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Run domain Beclin-1-interacting and cysteine-rich domain-containing protein (RUBCN).	[9]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Run domain Beclin-1-interacting and cysteine-rich domain-containing protein (RUBCN).	[10]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Run domain Beclin-1-interacting and cysteine-rich domain-containing protein (RUBCN).	[11]
APR-246	DMNFADH	Phase 2	APR-246 affects the expression of Run domain Beclin-1-interacting and cysteine-rich domain-containing protein (RUBCN).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Run domain Beclin-1-interacting and cysteine-rich domain-containing protein (RUBCN).	[14]

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 Run domain Beclin-1-interacting and cysteine-rich domain-containing protein (RUBCN).	[13]

References

• [1] Rundataxin, a novel protein with RUN and diacylglycerol binding domains, is mutant in a new recessive ataxia.Brain. 2010 Aug;133(Pt 8):2439-47. doi: 10.1093/brain/awq181.
• [2] Inducible Rubicon facilitates viral replication by antagonizing interferon production.Cell Mol Immunol. 2017 Jul;14(7):607-620. doi: 10.1038/cmi.2017.1. Epub 2017 Apr 10.
• [3] Podocytes and autophagy: a potential therapeutic target in lupus nephritis.Autophagy. 2019 May;15(5):908-912. doi: 10.1080/15548627.2019.1580512. Epub 2019 Feb 17.
• [4] The Salih ataxia mutation impairs Rubicon endosomal localization. Cerebellum. 2013 Dec;12(6):835-40. doi: 10.1007/s12311-013-0489-4.
• [5] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [6] 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.
• [7] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [8] 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.
• [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] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [11] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [12] Mutant p53 reactivation by PRIMA-1MET induces multiple signaling pathways converging on apoptosis. Oncogene. 2010 Mar 4;29(9):1329-38. doi: 10.1038/onc.2009.425. Epub 2009 Nov 30.
• [13] 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.
• [14] 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.