Details of Drug Off-Target (DOT)

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

• DOT Name: E3 ubiquitin-protein ligase pellino homolog 1 (PELI1)
• Synonyms: Pellino-1; EC 2.3.2.27; Pellino-related intracellular-signaling molecule; RING-type E3 ubiquitin transferase pellino homolog 1
• Gene Name: PELI1
• Related Disease:
  Cutaneous melanoma
  Delirium
  Melanoma
  Acute myelogenous leukaemia
  Adenocarcinoma
  Alzheimer disease
  Anxiety
  Anxiety disorder
  Atrial fibrillation
  Autoimmune disease
  Chorioamnionitis
  Classic phenylketonuria
  Euthyroid goiter
  Gastroesophageal reflux disease
  Hepatitis C virus infection
  Hypertrophic cardiomyopathy
  Irritable bowel syndrome
  Long QT syndrome
  Lung adenocarcinoma
  Lung cancer
  Lung carcinoma
  Lung neoplasm
  Myocardial infarction
  Parkinson disease
  Prostate cancer
  Prostate carcinoma
  Skin disease
  Stroke
  Chronic obstructive pulmonary disease
  Neoplasm
  Pulmonary disease
  Thyroid cancer
  Thyroid gland carcinoma
  Thyroid tumor
  Type-1/2 diabetes
  Advanced cancer
  Ebola virus infection
  Encephalitis
  Nervous system disease
  Nervous system inflammation
  Non-insulin dependent diabetes
  Phenylketonuria
  Subarachnoid hemorrhage
  Type-1 diabetes
  Tyrosinemia
• UniProt ID: PELI1_HUMAN
• EC Number: 2.3.2.27
• Pfam ID: PF04710 ; PF20723
• Sequence:
  MFSPDQENHPSKAPVKYGELIVLGYNGSLPNGDRGRRKSRFALFKRPKANGVKPSTVHIA
  CTPQAAKAISNKDQHSISYTLSRAQTVVVEYTHDSNTDMFQIGRSTESPIDFVVTDTVPG
  SQSNSDTQSVQSTISRFACRIICERNPPFTARIYAAGFDSSKNIFLGEKAAKWKTSDGQM
  DGLTTNGVLVMHPRNGFTEDSKPGIWREISVCGNVFSLRETRSAQQRGKMVEIETNQLQD
  GSLIDLCGATLLWRTAEGLSHTPTVKHLEALRQEINAARPQCPVGFNTLAFPSMKRKDVV
  DEKQPWVYLNCGHVHGYHNWGNKEERDGKDRECPMCRSVGPYVPLWLGCEAGFYVDAGPP
  THAFSPCGHVCSEKTTAYWSQIPLPHGTHTFHAACPFCAHQLAGEQGYIRLIFQGPLD
• Function: E3 ubiquitin ligase catalyzing the covalent attachment of ubiquitin moieties onto substrate proteins. Involved in the TLR and IL-1 signaling pathways via interaction with the complex containing IRAK kinases and TRAF6. Mediates 'Lys-63'-linked polyubiquitination of IRAK1 allowing subsequent NF-kappa-B activation. Mediates 'Lys-48'-linked polyubiquitination of RIPK3 leading to its subsequent proteasome-dependent degradation; preferentially recognizes and mediates the degradation of the 'Thr-182' phosphorylated form of RIPK3. Negatively regulates necroptosis by reducing RIPK3 expression. Mediates 'Lys-63'-linked ubiquitination of RIPK1.
• Tissue Specificity: Expressed at high levels in normal skin but decreased in keratinocytes from toxic epidermal necrolysis (TEN) patients (at protein level).
• Reactome Pathway:
  Interleukin-1 signaling (R-HSA-9020702)
  IRAK1 recruits IKK complex (R-HSA-937039)
  IRAK1 recruits IKK complex upon TLR7/8 or 9 stimulation (R-HSA-975144)
  Regulation of necroptotic cell death (R-HSA-5675482)

Molecular Interaction Atlas (MIA) of This DOT

45 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cutaneous melanoma	DIS3MMH9	Definitive	Altered Expression	[1]
Delirium	DIS2OKP1	Definitive	Genetic Variation	[2]
Melanoma	DIS1RRCY	Definitive	Altered Expression	[1]
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[3]
Adenocarcinoma	DIS3IHTY	Strong	Biomarker	[4]
Alzheimer disease	DISF8S70	Strong	Biomarker	[5]
Anxiety	DISIJDBA	Strong	Genetic Variation	[6]
Anxiety disorder	DISBI2BT	Strong	Genetic Variation	[6]
Atrial fibrillation	DIS15W6U	Strong	Biomarker	[7]
Autoimmune disease	DISORMTM	Strong	Biomarker	[8]
Chorioamnionitis	DISL1D9U	Strong	Altered Expression	[9]
Classic phenylketonuria	DISLU64N	Strong	Altered Expression	[10]
Euthyroid goiter	DISLRPYJ	Strong	Genetic Variation	[11]
Gastroesophageal reflux disease	DISQ8G5S	Strong	Biomarker	[12]
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[13]
Hypertrophic cardiomyopathy	DISQG2AI	Strong	Genetic Variation	[14]
Irritable bowel syndrome	DIS27206	Strong	Genetic Variation	[6]
Long QT syndrome	DISMKWS3	Strong	Genetic Variation	[14]
Lung adenocarcinoma	DISD51WR	Strong	Altered Expression	[4]
Lung cancer	DISCM4YA	Strong	Biomarker	[4]
Lung carcinoma	DISTR26C	Strong	Biomarker	[4]
Lung neoplasm	DISVARNB	Strong	Biomarker	[4]
Myocardial infarction	DIS655KI	Strong	Biomarker	[15]
Parkinson disease	DISQVHKL	Strong	Biomarker	[16]
Prostate cancer	DISF190Y	Strong	Biomarker	[17]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[17]
Skin disease	DISDW8R6	Strong	Biomarker	[18]
Stroke	DISX6UHX	Strong	Altered Expression	[7]
Chronic obstructive pulmonary disease	DISQCIRF	moderate	Biomarker	[19]
Neoplasm	DISZKGEW	moderate	Biomarker	[3]
Pulmonary disease	DIS6060I	moderate	Biomarker	[19]
Thyroid cancer	DIS3VLDH	Disputed	Biomarker	[20]
Thyroid gland carcinoma	DISMNGZ0	Disputed	Biomarker	[20]
Thyroid tumor	DISLVKMD	Disputed	Biomarker	[20]
Type-1/2 diabetes	DISIUHAP	Disputed	Biomarker	[21]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[1]
Ebola virus infection	DISJAVM1	Limited	Biomarker	[22]
Encephalitis	DISLD1RL	Limited	Biomarker	[23]
Nervous system disease	DISJ7GGT	Limited	Altered Expression	[24]
Nervous system inflammation	DISB3X5A	Limited	Biomarker	[23]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Genetic Variation	[25]
Phenylketonuria	DISCU56J	Limited	Biomarker	[26]
Subarachnoid hemorrhage	DISI7I8Y	Limited	Altered Expression	[27]
Type-1 diabetes	DIS7HLUB	Limited	Genetic Variation	[28]
Tyrosinemia	DISI8Q9Q	Limited	Altered Expression	[24]

23 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 E3 ubiquitin-protein ligase pellino homolog 1 (PELI1).	[29]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of E3 ubiquitin-protein ligase pellino homolog 1 (PELI1).	[30]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of E3 ubiquitin-protein ligase pellino homolog 1 (PELI1).	[31]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of E3 ubiquitin-protein ligase pellino homolog 1 (PELI1).	[32]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of E3 ubiquitin-protein ligase pellino homolog 1 (PELI1).	[33]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of E3 ubiquitin-protein ligase pellino homolog 1 (PELI1).	[34]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of E3 ubiquitin-protein ligase pellino homolog 1 (PELI1).	[35]
Arsenic	DMTL2Y1	Approved	Arsenic decreases the expression of E3 ubiquitin-protein ligase pellino homolog 1 (PELI1).	[18]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of E3 ubiquitin-protein ligase pellino homolog 1 (PELI1).	[37]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of E3 ubiquitin-protein ligase pellino homolog 1 (PELI1).	[38]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of E3 ubiquitin-protein ligase pellino homolog 1 (PELI1).	[39]
Cytarabine	DMZD5QR	Approved	Cytarabine increases the expression of E3 ubiquitin-protein ligase pellino homolog 1 (PELI1).	[40]
Cyclophosphamide	DM4O2Z7	Approved	Cyclophosphamide decreases the expression of E3 ubiquitin-protein ligase pellino homolog 1 (PELI1).	[37]
Lindane	DMB8CNL	Approved	Lindane increases the expression of E3 ubiquitin-protein ligase pellino homolog 1 (PELI1).	[37]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of E3 ubiquitin-protein ligase pellino homolog 1 (PELI1).	[41]
Phenol	DM1QSM3	Phase 2/3	Phenol increases the expression of E3 ubiquitin-protein ligase pellino homolog 1 (PELI1).	[42]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of E3 ubiquitin-protein ligase pellino homolog 1 (PELI1).	[43]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of E3 ubiquitin-protein ligase pellino homolog 1 (PELI1).	[37]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of E3 ubiquitin-protein ligase pellino homolog 1 (PELI1).	[44]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of E3 ubiquitin-protein ligase pellino homolog 1 (PELI1).	[45]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of E3 ubiquitin-protein ligase pellino homolog 1 (PELI1).	[38]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of E3 ubiquitin-protein ligase pellino homolog 1 (PELI1).	[38]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of E3 ubiquitin-protein ligase pellino homolog 1 (PELI1).	[46]

References

• [1] Peli1 Modulates the Subcellular Localization and Activity of Mdmx.Cancer Res. 2018 Jun 1;78(11):2897-2910. doi: 10.1158/0008-5472.CAN-17-3531. Epub 2018 Mar 9.
• [2] CE: Original Research: Recognizing Delirium in Hospitalized Children: A Systematic Review of the Evidence on Risk Factors and Characteristics.Am J Nurs. 2018 Apr;118(4):24-36. doi: 10.1097/01.NAJ.0000532069.55339.f9.
• [3] PRISM: methylation pattern-based, reference-free inference of subclonal makeup.Bioinformatics. 2019 Jul 15;35(14):i520-i529. doi: 10.1093/bioinformatics/btz327.
• [4] Pellino-1 promotes lung carcinogenesis via the stabilization of Slug and Snail through K63-mediated polyubiquitination.Cell Death Differ. 2017 Mar;24(3):469-480. doi: 10.1038/cdd.2016.143. Epub 2016 Dec 23.
• [5] Relating constructs of attention and working memory to social withdrawal in Alzheimer's disease and schizophrenia: issues regarding paradigm selection.Neurosci Biobehav Rev. 2019 Feb;97:47-69. doi: 10.1016/j.neubiorev.2018.09.025. Epub 2018 Nov 3.
• [6] A Measure of Suffering in relation to Anxiety and Quality of Life in IBS Patients: Preliminary Results.Biomed Res Int. 2017;2017:2387681. doi: 10.1155/2017/2387681. Epub 2017 Jul 4.
• [7] Cardioembolic Ischemic Stroke Gene Expression Fingerprint in Blood: a Systematic Review and Verification Analysis.Transl Stroke Res. 2020 Jun;11(3):326-336. doi: 10.1007/s12975-019-00730-x. Epub 2019 Sep 2.
• [8] Peli1 negatively regulates noncanonical NF-B signaling to restrain systemic lupus erythematosus.Nat Commun. 2018 Mar 19;9(1):1136. doi: 10.1038/s41467-018-03530-3.
• [9] Pellino 1 is a novel regulator of TNF and TLR signalling in human myometrial and amnion cells.J Reprod Immunol. 2018 Jun;127:24-35. doi: 10.1016/j.jri.2018.04.003. Epub 2018 Apr 14.
• [10] Pegvaliase: First Global Approval.BioDrugs. 2018 Aug;32(4):391-395. doi: 10.1007/s40259-018-0292-3.
• [11] Analysis of correlation between the process of thyroid fibrosis and TGFB1 gene expression level in fine-needle aspiration biopsy (FNAB) thyroid specimens collected from patients with Hashimoto's thyroiditis and non-toxic goitre.Exp Clin Endocrinol Diabetes. 2010 Jul;118(7):420-6. doi: 10.1055/s-0029-1225614. Epub 2010 Feb 26.
• [12] PRISM, a Patient-Reported Outcome Instrument, Accurately Measures Symptom Change in Refractory Gastroesophageal Reflux Disease.Dig Dis Sci. 2017 Mar;62(3):593-606. doi: 10.1007/s10620-016-4440-7. Epub 2017 Jan 23.
• [13] Anti-HCV immunoblot indeterminate results in blood donors: non-specific reactivity or past exposure to HCV?.Vox Sang. 2017 Aug;112(6):542-548. doi: 10.1111/vox.12547.
• [14] High-throughput single-strand conformation polymorphism analysis by automated capillary electrophoresis: robust multiplex analysis and pattern-based identification of allelic variants.Hum Mutat. 1999;13(4):318-27. doi: 10.1002/(SICI)1098-1004(1999)13:4<318::AID-HUMU9>3.0.CO;2-F.
• [15] Disruption of VEGF Mediated Flk-1 Signaling Leads to a Gradual Loss of Vessel Health and CardiacFunction During Myocardial Infarction: Potential Therapy With Pellino-1.J Am Heart Assoc. 2018 Sep 18;7(18):e007601. doi: 10.1161/JAHA.117.007601.
• [16] Peli1 controls the survival of dopaminergic neurons through modulating microglia-mediated neuroinflammation.Sci Rep. 2019 May 29;9(1):8034. doi: 10.1038/s41598-019-44573-w.
• [17] Quantification of mutant SPOP proteins in prostate cancer using mass spectrometry-based targeted proteomics.J Transl Med. 2017 Aug 15;15(1):175. doi: 10.1186/s12967-017-1276-7.
• [18] Gene expression profiles in peripheral lymphocytes by arsenic exposure and skin lesion status in a Bangladeshi population. Cancer Epidemiol Biomarkers Prev. 2006 Jul;15(7):1367-75. doi: 10.1158/1055-9965.EPI-06-0106.
• [19] Pellino-1 Regulates Immune Responses to Haemophilus influenzae in Models of Inflammatory Lung Disease.Front Immunol. 2019 Jul 31;10:1721. doi: 10.3389/fimmu.2019.01721. eCollection 2019.
• [20] Pictorial Representation of Illness and Self Measure-Revised 2 (PRISM-R2): an effective tool to assess perceived burden of thyroid cancer in mainland China.Support Care Cancer. 2018 Sep;26(9):3267-3275. doi: 10.1007/s00520-018-4172-7. Epub 2018 Apr 11.
• [21] Peli1 induction impairs cardiac microvascular endothelium through Hsp90 dissociation from IRE1.Biochim Biophys Acta Mol Basis Dis. 2019 Oct 1;1865(10):2606-2617. doi: 10.1016/j.bbadis.2019.06.017. Epub 2019 Jun 29.
• [22] Development and evaluation of a fluorogenic 5' nuclease assay to detect and differentiate between Ebola virus subtypes Zaire and Sudan.J Clin Microbiol. 2001 Nov;39(11):4125-30. doi: 10.1128/JCM.39.11.4125-4130.2001.
• [23] Peli1 facilitates virus replication and promotes neuroinflammation during West Nile virus infection.J Clin Invest. 2018 Nov 1;128(11):4980-4991. doi: 10.1172/JCI99902. Epub 2018 Sep 24.
• [24] HPD degradation regulated by the TTC36-STK33-PELI1 signaling axis induces tyrosinemia and neurological damage.Nat Commun. 2019 Sep 19;10(1):4266. doi: 10.1038/s41467-019-12011-0.
• [25] The rs7204609 polymorphism in the fat mass and obesity-associated gene is positively associated with central obesity and microalbuminuria in patients with type 2 diabetes from Southern Brazil.J Ren Nutr. 2012 Mar;22(2):228-236. doi: 10.1053/j.jrn.2011.03.004. Epub 2011 Jul 13.
• [26] Pegvaliase for the treatment of phenylketonuria: A pivotal, double-blind randomized discontinuation Phase 3 clinical trial.Mol Genet Metab. 2018 May;124(1):20-26. doi: 10.1016/j.ymgme.2018.03.003. Epub 2018 Mar 18.
• [27] Peli1 Contributions in Microglial Activation, Neuroinflammatory Responses and Neurological Deficits Following Experimental Subarachnoid Hemorrhage.Front Mol Neurosci. 2017 Nov 30;10:398. doi: 10.3389/fnmol.2017.00398. eCollection 2017.
• [28] CTLA-4 CT60 polymorphism in thyroid and polyglandular autoimmunity.Horm Metab Res. 2009 Jun;41(6):426-9. doi: 10.1055/s-0029-1214414.
• [29] 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.
• [30] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [31] 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.
• [32] 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.
• [33] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [34] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [35] Long-term estrogen exposure promotes carcinogen bioactivation, induces persistent changes in gene expression, and enhances the tumorigenicity of MCF-7 human breast cancer cells. Toxicol Appl Pharmacol. 2009 Nov 1;240(3):355-66.
• [36] Gene expression profiles in peripheral lymphocytes by arsenic exposure and skin lesion status in a Bangladeshi population. Cancer Epidemiol Biomarkers Prev. 2006 Jul;15(7):1367-75. doi: 10.1158/1055-9965.EPI-06-0106.
• [37] Transcriptome-based functional classifiers for direct immunotoxicity. Arch Toxicol. 2014 Mar;88(3):673-89.
• [38] Epigenetic influences of low-dose bisphenol A in primary human breast epithelial cells. Toxicol Appl Pharmacol. 2010 Oct 15;248(2):111-21.
• [39] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [40] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [41] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [42] Classification of heavy-metal toxicity by human DNA microarray analysis. Environ Sci Technol. 2007 May 15;41(10):3769-74.
• [43] 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.
• [44] BET bromodomain inhibition targets both c-Myc and IL7R in high-risk acute lymphoblastic leukemia. Blood. 2012 Oct 4;120(14):2843-52.
• [45] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [46] Sulforaphane-induced apoptosis in human leukemia HL-60 cells through extrinsic and intrinsic signal pathways and altering associated genes expression assayed by cDNA microarray. Environ Toxicol. 2017 Jan;32(1):311-328.