Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT4BZONL)

• DOT Name: E3 ubiquitin-protein ligase RNF31 (RNF31)
• Synonyms: EC 2.3.2.31; HOIL-1-interacting protein; HOIP; RING finger protein 31; RING-type E3 ubiquitin transferase RNF31; Zinc in-between-RING-finger ubiquitin-associated domain protein
• Gene Name: RNF31
• Related Disease:
  Adrenocortical carcinoma
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Dermatitis
  Glycogen storage disease due to glycogen branching enzyme deficiency
  Neoplasm
  Pituitary adenoma
  Prostate cancer
  Prostate neoplasm
  Autoinflammatory syndrome with pyogenic bacterial infection and amylopectinosis
  Gastric cancer
  Polyglucosan body myopathy 1 with or without immunodeficiency
  Stomach cancer
• UniProt ID: RNF31_HUMAN
• PDB ID: 2CT7; 4DBG; 4JUY; 4LJO; 4LJP; 4LJQ; 4OWF; 4OYJ; 4OYK; 4P09; 4P0A; 4P0B; 5EDV; 5LJN; 5X0W; 6GZY; 6KC5; 6KC6; 6SC5; 6SC6; 6SC7; 6SC8; 6SC9; 7TV4; 7UY2; 7UYJ; 7UYK; 7V8F; 7V8G
• EC Number: 2.3.2.31
• Pfam ID: PF18091 ; PF16678 ; PF01485 ; PF09409 ; PF18486
• Sequence:
  MPGEEEERAFLVAREELASALRRDSGQAFSLEQLRPLLASSLPLAARYLQLDAARLVRCN
  AHGEPRNYLNTLSTALNILEKYGRNLLSPQRPRYWRGVKFNNPVFRSTVDAVQGGRDVLR
  LYGYTEEQPDGLSFPEGQEEPDEHQVATVTLEVLLLRTELSLLLQNTHPRQQALEQLLED
  KVEDDMLQLSEFDPLLREIAPGPLTTPSVPGSTPGPCFLCGSAPGTLHCPSCKQALCPAC
  DHLFHGHPSRAHHLRQTLPGVLQGTHLSPSLPASAQPRPQSTSLLALGDSSLSSPNPASA
  HLPWHCAACAMLNEPWAVLCVACDRPRGCKGLGLGTEGPQGTGGLEPDLARGRWACQSCT
  FENEAAAVLCSICERPRLAQPPSLVVDSRDAGICLQPLQQGDALLASAQSQVWYCIHCTF
  CNSSPGWVCVMCNRTSSPIPAQHAPRPYASSLEKGPPKPGPPRRLSAPLPSSCGDPEKQR
  QDKMREEGLQLVSMIREGEAAGACPEEIFSALQYSGTEVPLQWLRSELPYVLEMVAELAG
  QQDPGLGAFSCQEARRAWLDRHGNLDEAVEECVRTRRRKVQELQSLGFGPEEGSLQALFQ
  HGGDVSRALTELQRQRLEPFRQRLWDSGPEPTPSWDGPDKQSLVRRLLAVYALPSWGRAE
  LALSLLQETPRNYELGDVVEAVRHSQDRAFLRRLLAQECAVCGWALPHNRMQALTSCECT
  ICPDCFRQHFTIALKEKHITDMVCPACGRPDLTDDTQLLSYFSTLDIQLRESLEPDAYAL
  FHKKLTEGVLMRDPKFLWCAQCSFGFIYEREQLEATCPQCHQTFCVRCKRQWEEQHRGRS
  CEDFQNWKRMNDPEYQAQGLAMYLQENGIDCPKCKFSYALARGGCMHFHCTQCRHQFCSG
  CYNAFYAKNKCPEPNCRVKKSLHGHHPRDCLFYLRDWTALRLQKLLQDNNVMFNTEPPAG
  ARAVPGGGCRVIEQKEVPNGLRDEACGKETPAGYAGLCQAHYKEYLVSLINAHSLDPATL
  YEVEELETATERYLHVRPQPLAGEDPPAYQARLLQKLTEEVPLGQSIPRRRK
• Function: E3 ubiquitin-protein ligase 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. Recruited to the surface of bacteria by RNF213, which initiates the bacterial ubiquitin coat. 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. RNF31 is required for linear ubiquitination of BCL10, thereby promoting TCR-induced NF-kappa-B activation. Binds polyubiquitin of different linkage types.
• Tissue Specificity: Expressed in both normal and transformed breast epithelial cell lines.
• 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)
  TNFR1-induced proapoptotic signaling (R-HSA-5357786)

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adrenocortical carcinoma	DISZF4HX	Strong	Biomarker	[1]
Breast cancer	DIS7DPX1	Strong	Biomarker	[2]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[2]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[3]
Dermatitis	DISY5SZC	Strong	Biomarker	[4]
Glycogen storage disease due to glycogen branching enzyme deficiency	DIS3H8HJ	Strong	Genetic Variation	[5]
Neoplasm	DISZKGEW	Strong	Biomarker	[6]
Pituitary adenoma	DISJ5R1X	Strong	Biomarker	[7]
Prostate cancer	DISF190Y	Strong	Biomarker	[8]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[8]
Autoinflammatory syndrome with pyogenic bacterial infection and amylopectinosis	DISJ79IN	Supportive	Autosomal recessive	[9]
Gastric cancer	DISXGOUK	Limited	Biomarker	[10]
Polyglucosan body myopathy 1 with or without immunodeficiency	DISKOIME	Limited	Biomarker	[9]
Stomach cancer	DISKIJSX	Limited	Biomarker	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Camptothecin	DM6CHNJ	Phase 3	E3 ubiquitin-protein ligase RNF31 (RNF31) decreases the response to substance of Camptothecin.	[16]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of E3 ubiquitin-protein ligase RNF31 (RNF31).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of E3 ubiquitin-protein ligase RNF31 (RNF31).	[12]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of E3 ubiquitin-protein ligase RNF31 (RNF31).	[13]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of E3 ubiquitin-protein ligase RNF31 (RNF31).	[14]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of E3 ubiquitin-protein ligase RNF31 (RNF31).	[15]

References

• [1] Knockdown of SF-1 and RNF31 affects components of steroidogenesis, TGFbeta, and Wnt/beta-catenin signaling in adrenocortical carcinoma cells. PLoS One. 2012;7(3):e32080.
• [2] Correction: The atypical ubiquitin ligase RNF31 stabilizes estrogen receptor and modulates estrogen-stimulated breast cancer cell proliferation.Oncogene. 2019 Jan;38(2):299-300. doi: 10.1038/s41388-018-0502-y.
• [3] Identification of the protein Zibra, its genomic organization, regulation, and expression in breast cancer cells.Exp Cell Res. 2004 May 1;295(2):448-59. doi: 10.1016/j.yexcr.2004.01.019.
• [4] RNF31 Regulates Skin Homeostasis by Protecting Epidermal Keratinocytes from Cell Death.J Immunol. 2018 Jun 15;200(12):4117-4124. doi: 10.4049/jimmunol.1800172. Epub 2018 May 4.
• [5] An Update on Autoinflammatory Diseases: Relopathies.Curr Rheumatol Rep. 2018 May 30;20(7):39. doi: 10.1007/s11926-018-0749-x.
• [6] Expression of the three components of linear ubiquitin assembly complex in breast cancer.PLoS One. 2018 May 15;13(5):e0197183. doi: 10.1371/journal.pone.0197183. eCollection 2018.
• [7] MicroRNA-378 regulates cell proliferation and migration by repressing RNF31 in pituitary adenoma.Oncol Lett. 2018 Jan;15(1):789-794. doi: 10.3892/ol.2017.7431. Epub 2017 Nov 16.
• [8] The long tail of oncogenic drivers in prostate cancer.Nat Genet. 2018 May;50(5):645-651. doi: 10.1038/s41588-018-0078-z. Epub 2018 Apr 2.
• [9] Human HOIP and LUBAC deficiency underlies autoinflammation, immunodeficiency, amylopectinosis, and lymphangiectasia. J Exp Med. 2015 Jun 1;212(6):939-51. doi: 10.1084/jem.20141130. Epub 2015 May 25.
• [10] Ring finger protein 31-mediated atypical ubiquitination stabilizes forkhead box P3 and thereby stimulates regulatory T-cell function.J Biol Chem. 2018 Dec 28;293(52):20099-20111. doi: 10.1074/jbc.RA118.005802. Epub 2018 Nov 2.
• [11] 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.
• [12] 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.
• [13] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [14] 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.
• [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.
• [16] ATR inhibitors VE-821 and VX-970 sensitize cancer cells to topoisomerase i inhibitors by disabling DNA replication initiation and fork elongation responses. Cancer Res. 2014 Dec 1;74(23):6968-79.