Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT5TQBGV)

• DOT Name: TNF receptor-associated factor 3 (TRAF3)
• Synonyms: EC 2.3.2.27; CD40 receptor-associated factor 1; CRAF1; CD40-binding protein; CD40BP; LMP1-associated protein 1; LAP1; RING-type E3 ubiquitin transferase TRAF3
• Gene Name: TRAF3
• Related Disease:
  Classic Hodgkin lymphoma
  Dystonia
  Rheumatoid arthritis
  Acute myelogenous leukaemia
  Adult lymphoma
  Advanced cancer
  Astrocytoma
  Autoimmune disease
  B-cell lymphoma
  B-cell neoplasm
  Breast cancer
  Breast carcinoma
  Carcinoma of liver and intrahepatic biliary tract
  Cervical cancer
  Cervical carcinoma
  Colitis
  Crohn disease
  Glioma
  Hepatocellular carcinoma
  Herpes simplex encephalitis
  Herpes simplex infection
  Inflammatory bowel disease
  Leukemia
  Liver cancer
  Lymphoma
  Multiple sclerosis
  Neoplasm
  Non-alcoholic fatty liver disease
  Non-hodgkin lymphoma
  Osteoarthritis
  Pediatric lymphoma
  Plasma cell myeloma
  Squamous cell carcinoma
  Ulcerative colitis
  Head-neck squamous cell carcinoma
  Influenza
  Muscular dystrophy
  TRAF3 haploinsufficiency
  Bone osteosarcoma
  Fatty liver disease
  Gastric cancer
  Nasopharyngeal carcinoma
  Non-insulin dependent diabetes
  Osteoporosis
  Osteosarcoma
  Stomach cancer
• UniProt ID: TRAF3_HUMAN
• PDB ID: 1FLK; 1FLL; 1KZZ; 1L0A; 1RF3; 1ZMS; 2ECY; 2GKW; 8T5P
• EC Number: 2.3.2.27
• Pfam ID: PF21355 ; PF21363 ; PF02176
• Sequence:
  MESSKKMDSPGALQTNPPLKLHTDRSAGTPVFVPEQGGYKEKFVKTVEDKYKCEKCHLVL
  CSPKQTECGHRFCESCMAALLSSSSPKCTACQESIVKDKVFKDNCCKREILALQIYCRNE
  SRGCAEQLMLGHLLVHLKNDCHFEELPCVRPDCKEKVLRKDLRDHVEKACKYREATCSHC
  KSQVPMIALQKHEDTDCPCVVVSCPHKCSVQTLLRSELSAHLSECVNAPSTCSFKRYGCV
  FQGTNQQIKAHEASSAVQHVNLLKEWSNSLEKKVSLLQNESVEKNKSIQSLHNQICSFEI
  EIERQKEMLRNNESKILHLQRVIDSQAEKLKELDKEIRPFRQNWEEADSMKSSVESLQNR
  VTELESVDKSAGQVARNTGLLESQLSRHDQMLSVHDIRLADMDLRFQVLETASYNGVLIW
  KIRDYKRRKQEAVMGKTLSLYSQPFYTGYFGYKMCARVYLNGDGMGKGTHLSLFFVIMRG
  EYDALLPWPFKQKVTLMLMDQGSSRRHLGDAFKPDPNSSSFKKPTGEMNIASGCPVFVAQ
  TVLENGTYIKDDTIFIKVIVDTSDLPDP
• Function: Cytoplasmic E3 ubiquitin ligase that regulates various signaling pathways, such as the NF-kappa-B, mitogen-activated protein kinase (MAPK) and interferon regulatory factor (IRF) pathways, and thus controls a lot of biological processes in both immune and non-immune cell types. In TLR and RLR signaling pathways, acts as an E3 ubiquitin ligase promoting the synthesis of 'Lys-63'-linked polyubiquitin chains on several substrates such as ASC that lead to the activation of the type I interferon response or the inflammasome. Following the activation of certain TLRs such as TLR4, acts as a negative NF-kappa-B regulator, possibly to avoid unregulated inflammatory response, and its degradation via 'Lys-48'-linked polyubiquitination is required for MAPK activation and production of inflammatory cytokines. Alternatively, when TLR4 orchestrates bacterial expulsion, TRAF3 undergoes 'Lys-33'-linked polyubiquitination and subsequently binds to RALGDS, mobilizing the exocyst complex to rapidly expel intracellular bacteria back for clearance. Acts also as a constitutive negative regulator of the alternative NF-kappa-B pathway, which controls B-cell survival and lymphoid organ development. Required for normal antibody isotype switching from IgM to IgG. Plays a role T-cell dependent immune responses. Down-regulates proteolytic processing of NFKB2, and thereby inhibits non-canonical activation of NF-kappa-B. Promotes ubiquitination and proteasomal degradation of MAP3K14.
• KEGG Pathway:
  NF-kappa B sig.ling pathway (hsa04064)
  Toll-like receptor sig.ling pathway (hsa04620)
  NOD-like receptor sig.ling pathway (hsa04621)
  RIG-I-like receptor sig.ling pathway (hsa04622)
  IL-17 sig.ling pathway (hsa04657)
  TNF sig.ling pathway (hsa04668)
  Alcoholic liver disease (hsa04936)
  Hepatitis C (hsa05160)
  Hepatitis B (hsa05161)
  Measles (hsa05162)
  Influenza A (hsa05164)
  Human papillomavirus infection (hsa05165)
  Kaposi sarcoma-associated herpesvirus infection (hsa05167)
  Herpes simplex virus 1 infection (hsa05168)
  Epstein-Barr virus infection (hsa05169)
  Coro.virus disease - COVID-19 (hsa05171)
  Pathways in cancer (hsa05200)
  Viral carcinogenesis (hsa05203)
  Small cell lung cancer (hsa05222)
  Lipid and atherosclerosis (hsa05417)
• Reactome Pathway:
  TNFR2 non-canonical NF-kB pathway (R-HSA-5668541)
  TNF receptor superfamily (TNFSF) members mediating non-canonical NF-kB pathway (R-HSA-5676594)
  Ovarian tumor domain proteases (R-HSA-5689896)
  TICAM1-dependent activation of IRF3/IRF7 (R-HSA-9013973)
  TRAF3-dependent IRF activation pathway (R-HSA-918233)
  Negative regulators of DDX58/IFIH1 signaling (R-HSA-936440)
  Activation of IRF3, IRF7 mediated by TBK1, IKK (IKBKE) (R-HSA-936964)
  SARS-CoV-1 activates/modulates innate immune responses (R-HSA-9692916)
  SARS-CoV-2 activates/modulates innate and adaptive immune responses (R-HSA-9705671)
  TRAF3 deficiency - HSE (R-HSA-5602571)

Molecular Interaction Atlas (MIA) of This DOT

46 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Classic Hodgkin lymphoma	DISV1LU6	Definitive	Altered Expression	[1]
Dystonia	DISJLFGW	Definitive	Biomarker	[2]
Rheumatoid arthritis	DISTSB4J	Definitive	Biomarker	[3]
Acute myelogenous leukaemia	DISCSPTN	Strong	Genetic Variation	[4]
Adult lymphoma	DISK8IZR	Strong	Biomarker	[5]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[6]
Astrocytoma	DISL3V18	Strong	Biomarker	[7]
Autoimmune disease	DISORMTM	Strong	Biomarker	[8]
B-cell lymphoma	DISIH1YQ	Strong	Altered Expression	[9]
B-cell neoplasm	DISVY326	Strong	Altered Expression	[10]
Breast cancer	DIS7DPX1	Strong	Biomarker	[11]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[11]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Strong	Biomarker	[12]
Cervical cancer	DISFSHPF	Strong	Genetic Variation	[13]
Cervical carcinoma	DIST4S00	Strong	Genetic Variation	[13]
Colitis	DISAF7DD	Strong	Altered Expression	[14]
Crohn disease	DIS2C5Q8	Strong	Altered Expression	[14]
Glioma	DIS5RPEH	Strong	Biomarker	[7]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[15]
Herpes simplex encephalitis	DISGX28I	Strong	Biomarker	[16]
Herpes simplex infection	DISL1SAV	Strong	Biomarker	[17]
Inflammatory bowel disease	DISGN23E	Strong	Biomarker	[14]
Leukemia	DISNAKFL	Strong	Genetic Variation	[18]
Liver cancer	DISDE4BI	Strong	Biomarker	[12]
Lymphoma	DISN6V4S	Strong	Biomarker	[5]
Multiple sclerosis	DISB2WZI	Strong	Genetic Variation	[19]
Neoplasm	DISZKGEW	Strong	Biomarker	[6]
Non-alcoholic fatty liver disease	DISDG1NL	Strong	Biomarker	[20]
Non-hodgkin lymphoma	DISS2Y8A	Strong	Altered Expression	[21]
Osteoarthritis	DIS05URM	Strong	Biomarker	[22]
Pediatric lymphoma	DIS51BK2	Strong	Biomarker	[5]
Plasma cell myeloma	DIS0DFZ0	Strong	Biomarker	[10]
Squamous cell carcinoma	DISQVIFL	Strong	Biomarker	[8]
Ulcerative colitis	DIS8K27O	Strong	Altered Expression	[14]
Head-neck squamous cell carcinoma	DISF7P24	moderate	Genetic Variation	[23]
Influenza	DIS3PNU3	moderate	Biomarker	[24]
Muscular dystrophy	DISJD6P7	moderate	Biomarker	[25]
TRAF3 haploinsufficiency	DISQDHX4	Moderate	Autosomal dominant	[26]
Bone osteosarcoma	DIST1004	Limited	Altered Expression	[27]
Fatty liver disease	DIS485QZ	Limited	Biomarker	[28]
Gastric cancer	DISXGOUK	Limited	Biomarker	[29]
Nasopharyngeal carcinoma	DISAOTQ0	Limited	Biomarker	[30]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Genetic Variation	[31]
Osteoporosis	DISF2JE0	Limited	Biomarker	[32]
Osteosarcoma	DISLQ7E2	Limited	Altered Expression	[27]
Stomach cancer	DISKIJSX	Limited	Biomarker	[29]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ibrutinib	DMHZCPO	Approved	TNF receptor-associated factor 3 (TRAF3) decreases the response to substance of Ibrutinib.	[51]

3 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 TNF receptor-associated factor 3 (TRAF3).	[33]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of TNF receptor-associated factor 3 (TRAF3).	[38]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of TNF receptor-associated factor 3 (TRAF3).	[47]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of TNF receptor-associated factor 3 (TRAF3).	[34]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of TNF receptor-associated factor 3 (TRAF3).	[35]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of TNF receptor-associated factor 3 (TRAF3).	[36]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of TNF receptor-associated factor 3 (TRAF3).	[37]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of TNF receptor-associated factor 3 (TRAF3).	[39]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of TNF receptor-associated factor 3 (TRAF3).	[40]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of TNF receptor-associated factor 3 (TRAF3).	[41]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of TNF receptor-associated factor 3 (TRAF3).	[42]
Menthol	DMG2KW7	Approved	Menthol increases the expression of TNF receptor-associated factor 3 (TRAF3).	[43]
Capsaicin	DMGMF6V	Approved	Capsaicin increases the expression of TNF receptor-associated factor 3 (TRAF3).	[44]
Hydroxychloroquine	DMSIVND	Approved	Hydroxychloroquine increases the expression of TNF receptor-associated factor 3 (TRAF3).	[45]
Curcumin	DMQPH29	Phase 3	Curcumin increases the expression of TNF receptor-associated factor 3 (TRAF3).	[46]
Taxifolin	DMQJSF9	Preclinical	Taxifolin increases the expression of TNF receptor-associated factor 3 (TRAF3).	[48]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of TNF receptor-associated factor 3 (TRAF3).	[49]
Paraquat	DMR8O3X	Investigative	Paraquat decreases the expression of TNF receptor-associated factor 3 (TRAF3).	[50]

References

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• [18] Somatic mutation of TRAF3 gene is rare in common human cancers and acute leukemias.Acta Oncol. 2008;47(8):1615-7. doi: 10.1080/02841860802195277.
• [19] Evidence from genome wide association studies implicates reduced control of Epstein-Barr virus infection in multiple sclerosis susceptibility.Genome Med. 2019 Apr 30;11(1):26. doi: 10.1186/s13073-019-0640-z.
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• [22] WITHDRAWN: MicroRNA-107 regulates autophagy and apoptosis of osteoarthritis chondrocytes by targeting TRAF3.Int Immunopharmacol. 2019 Jun;71:181-187. doi: 10.1016/j.intimp.2019.03.005. Epub 2019 Mar 22.
• [23] TRAF3/CYLD mutations identify a distinct subset of human papillomavirus-associated head and neck squamous cell carcinoma.Cancer. 2017 May 15;123(10):1778-1790. doi: 10.1002/cncr.30570. Epub 2017 Mar 13.
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• [27] MicroRNA-214 functions as an oncogene in human osteosarcoma by targeting TRAF3.Eur Rev Med Pharmacol Sci. 2018 Aug;22(16):5156-5164. doi: 10.26355/eurrev_201808_15711.
• [28] An unbiased approach de-livers unexpected insight into torsin biology.J Clin Invest. 2019 Nov 1;129(11):4576-4579. doi: 10.1172/JCI132442.
• [29] miR-17-92 functions as an oncogene and modulates NF-B signaling by targeting TRAF3 in MGC-803 human gastric cancer cells.Int J Oncol. 2018 Nov;53(5):2241-2257. doi: 10.3892/ijo.2018.4543. Epub 2018 Aug 28.
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• [32] TGF-induced degradation of TRAF3 in mesenchymal progenitor cells causes age-related osteoporosis.Nat Commun. 2019 Jun 26;10(1):2795. doi: 10.1038/s41467-019-10677-0.
• [33] 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.
• [34] 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.
• [35] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [36] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
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• [48] The chemopreventive effect of taxifolin is exerted through ARE-dependent gene regulation. Biol Pharm Bull. 2007 Jun;30(6):1074-9.
• [49] Genome-wide expression changes induced by bisphenol A, F and S in human stem cell derived hepatocyte-like cells. EXCLI J. 2020 Nov 4;19:1459-1476. doi: 10.17179/excli2020-2934. eCollection 2020.
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• [51] Synergistic activity of BET protein antagonist-based combinations in mantle cell lymphoma cells sensitive or resistant to ibrutinib. Blood. 2015 Sep 24;126(13):1565-74.