Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT18NH5N)

• DOT Name: E3 ubiquitin-protein ligase RNF135 (RNF135)
• Synonyms: EC 2.3.2.27; RIG-I E3 ubiquitin ligase; REUL; RING finger protein 135; RING finger protein leading to RIG-I activation; Riplet; RING-type E3 ubiquitin transferase RNF135
• Gene Name: RNF135
• Related Disease:
  Advanced cancer
  Autism
  Autism spectrum disorder
  Malignant peripheral nerve sheath tumor
  Neurofibromatosis type 1
  Obsolete overgrowth-macrocephaly-facial dysmorphism syndrome
  Overgrowth syndrome
• UniProt ID: RN135_HUMAN
• PDB ID: 7JL1; 7JL3; 8G7T; 8G7U; 8G7V
• EC Number: 2.3.2.27
• Pfam ID: PF00622 ; PF15227
• Sequence:
  MAGLGLGSAVPVWLAEDDLGCIICQGLLDWPATLPCGHSFCRHCLEALWGARDARRWACP
  TCRQGAAQQPHLRKNTLLQDLADKYRRAAREIQAGSDPAHCPCPGSSSLSSAAARPRRRP
  ELQRVAVEKSITEVAQELTELVEHLVDIVRSLQNQRPLSESGPDNELSILGKAFSSGVDL
  SMASPKLVTSDTAAGKIRDILHDLEEIQEKLQESVTWKEAPEAQMQGELLEAPSSSSCPL
  PDQSHPALRRASRFAQWAIHPTFNLKSLSCSLEVSKDSRTVTVSHRPQPYRWSCERFSTS
  QVLCSQALSSGKHYWEVDTRNCSHWAVGVASWEMSRDQVLGRTMDSCCVEWKGTSQLSAW
  HMVKETVLGSDRPGVVGIWLNLEEGKLAFYSVDNQEKLLYECTISASSPLYPAFWLYGLH
  PGNYLIIKQVKV
• Function: E2-dependent E3 ubiquitin-protein ligase that functions as a RIGI coreceptor in the sensing of viral RNAs in cell cytoplasm and the activation of the antiviral innate immune response. Together with the UBE2D3, UBE2N and UB2V1 E2 ligases, catalyzes the 'Lys-63'-linked polyubiquitination of RIGI oligomerized on viral RNAs, an essential step in the activation of the RIG-I signaling pathway. Through a ubiquitin-independent parallel mechanism, which consists in bridging RIGI filaments forming on longer viral RNAs, further activates the RIG-I signaling pathway. This second mechanism that synergizes with the ubiquitin-dependent one would thereby allow an RNA length-dependent regulation of the RIG-I signaling pathway (Probable). Associated with the E2 ligase UBE2N, also constitutively synthesizes unanchored 'Lys-63'-linked polyubiquitin chains that may also activate the RIG-I signaling pathway.
• Tissue Specificity: Expressed in skeletal muscle, spleen, kidney, placenta, prostate, stomach, thyroid and tongue. Also weakly expressed in heart, thymus, liver and lung.
• Reactome Pathway:
  Ovarian tumor domain proteases (R-HSA-5689896)
  TRAF3-dependent IRF activation pathway (R-HSA-918233)
  TRAF6 mediated IRF7 activation (R-HSA-933541)
  TRAF6 mediated NF-kB activation (R-HSA-933542)
  NF-kB activation through FADD/RIP-1 pathway mediated by caspase-8 and -10 (R-HSA-933543)
  Negative regulators of DDX58/IFIH1 signaling (R-HSA-936440)
  SARS-CoV-2 activates/modulates innate and adaptive immune responses (R-HSA-9705671)
  DDX58/IFIH1-mediated induction of interferon-alpha/beta (R-HSA-168928)

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Autism	DISV4V1Z	Strong	Genetic Variation	[2]
Autism spectrum disorder	DISXK8NV	Strong	CausalMutation	[3]
Malignant peripheral nerve sheath tumor	DIS0JTN6	Strong	Altered Expression	[1]
Neurofibromatosis type 1	DIS53JH9	moderate	Genetic Variation	[4]
Obsolete overgrowth-macrocephaly-facial dysmorphism syndrome	DIS0BVHE	Supportive	Autosomal dominant	[5]
Overgrowth syndrome	DISHK54G	Limited	Autosomal dominant	[6]

6 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 E3 ubiquitin-protein ligase RNF135 (RNF135).	[7]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of E3 ubiquitin-protein ligase RNF135 (RNF135).	[8]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of E3 ubiquitin-protein ligase RNF135 (RNF135).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of E3 ubiquitin-protein ligase RNF135 (RNF135).	[10]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of E3 ubiquitin-protein ligase RNF135 (RNF135).	[11]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of E3 ubiquitin-protein ligase RNF135 (RNF135).	[15]

3 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 increases the methylation of E3 ubiquitin-protein ligase RNF135 (RNF135).	[12]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of E3 ubiquitin-protein ligase RNF135 (RNF135).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of E3 ubiquitin-protein ligase RNF135 (RNF135).	[14]

References

• [1] Identification of genes potentially involved in the increased risk of malignancy in NF1-microdeleted patients.Mol Med. 2011 Jan-Feb;17(1-2):79-87. doi: 10.2119/molmed.2010.00079. Epub 2010 Sep 10.
• [2] Mutation screening of the ubiquitin ligase gene RNF135 in French patients with autism.Psychiatr Genet. 2015 Dec;25(6):263-7. doi: 10.1097/YPG.0000000000000100.
• [3] Targeted resequencing of 358 candidate genes for autism spectrum disorder in a Chinese cohort reveals diagnostic potential and genotype-phenotype correlations. Hum Mutat. 2019 Jun;40(6):801-815. doi: 10.1002/humu.23724. Epub 2019 Apr 29.
• [4] Identification of an atypical microdeletion generating the RNF135-SUZ12 chimeric gene and causing a position effect in an NF1 patient with overgrowth.Hum Genet. 2017 Oct;136(10):1329-1339. doi: 10.1007/s00439-017-1832-5. Epub 2017 Aug 3.
• [5] Mutations in RNF135, a gene within the NF1 microdeletion region, cause phenotypic abnormalities including overgrowth. Nat Genet. 2007 Aug;39(8):963-5. doi: 10.1038/ng2083. Epub 2007 Jul 15.
• [6] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [7] 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.
• [8] 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.
• [9] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [10] 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.
• [11] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [12] 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.
• [13] 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.
• [14] Expression and DNA methylation changes in human breast epithelial cells after bisphenol A exposure. Int J Oncol. 2012 Jul;41(1):369-77.
• [15] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.