Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTNC3XFD)

• DOT Name: Single Ig IL-1-related receptor (SIGIRR)
• Synonyms: Single Ig IL-1R-related molecule; Single immunoglobulin domain-containing IL1R-related protein; Toll/interleukin-1 receptor 8; TIR8
• Gene Name: SIGIRR
• Related Disease:
  Advanced cancer
  Allergic rhinitis
  Arteriosclerosis
  Atherosclerosis
  Autoimmune disease
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Depression
  HIV infectious disease
  Pneumonia
  Pneumonitis
  Rheumatoid arthritis
  Systemic sclerosis
  Tuberculosis
  Asthma
  Corneal infection
  Keratitis
  Bacterial vaginosis
  leukaemia
  Leukemia
  Neoplasm
  Small lymphocytic lymphoma
• UniProt ID: SIGIR_HUMAN
• Pfam ID: PF01582
• Sequence:
  MPGVCDRAPDFLSPSEDQVLRPALGSSVALNCTAWVVSGPHCSLPSVQWLKDGLPLGIGG
  HYSLHEYSWVKANLSEVLVSSVLGVNVTSTEVYGAFTCSIQNISFSSFTLQRAGPTSHVA
  AVLASLLVLLALLLAALLYVKCRLNVLLWYQDAYGEVEINDGKLYDAYVSYSDCPEDRKF
  VNFILKPQLERRRGYKLFLDDRDLLPRAEPSADLLVNLSRCRRLIVVLSDAFLSRAWCSH
  SFREGLCRLLELTRRPIFITFEGQRRDPAHPALRLLRQHRHLVTLLLWRPGSVTPSSDFW
  KEVQLALPRKVQYRPVEGDPQTQLQDDKDPMLILRGRVPEGRALDSEVDPDPEGDLGVRG
  PVFGEPSAPPHTSGVSLGESRSSEVDVSDLGSRNYSARTDFYCLVSKDDM
• Function: Acts as a negative regulator of the Toll-like and IL-1R receptor signaling pathways. Attenuates the recruitment of receptor-proximal signaling components to the TLR4 receptor, probably through an TIR-TIR domain interaction with TLR4. Through its extracellular domain interferes with the heterodimerization of Il1R1 and IL1RAP.
• Tissue Specificity: Mainly expressed in epithelial tissues such as kidney, lung and gut.
• Reactome Pathway:
  Interleukin-37 signaling (R-HSA-9008059)
  MyD88 (R-HSA-166058)

Molecular Interaction Atlas (MIA) of This DOT

23 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Allergic rhinitis	DIS3U9HN	Strong	Biomarker	[2]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[3]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[3]
Autoimmune disease	DISORMTM	Strong	Biomarker	[1]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[4]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[4]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[4]
Depression	DIS3XJ69	Strong	Altered Expression	[5]
HIV infectious disease	DISO97HC	Strong	Altered Expression	[6]
Pneumonia	DIS8EF3M	Strong	Biomarker	[7]
Pneumonitis	DIS88E0K	Strong	Biomarker	[7]
Rheumatoid arthritis	DISTSB4J	Strong	Biomarker	[8]
Systemic sclerosis	DISF44L6	Strong	Biomarker	[9]
Tuberculosis	DIS2YIMD	Strong	Genetic Variation	[10]
Asthma	DISW9QNS	moderate	Biomarker	[11]
Corneal infection	DISN2KPA	moderate	Biomarker	[12]
Keratitis	DISMFOEI	moderate	Biomarker	[12]
Bacterial vaginosis	DISK2MZ2	Limited	Biomarker	[13]
leukaemia	DISS7D1V	Limited	Biomarker	[14]
Leukemia	DISNAKFL	Limited	Biomarker	[14]
Neoplasm	DISZKGEW	Limited	Biomarker	[15]
Small lymphocytic lymphoma	DIS30POX	Limited	Altered Expression	[14]

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 Single Ig IL-1-related receptor (SIGIRR).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Single Ig IL-1-related receptor (SIGIRR).	[26]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Single Ig IL-1-related receptor (SIGIRR).	[28]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Single Ig IL-1-related receptor (SIGIRR).	[17]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Single Ig IL-1-related receptor (SIGIRR).	[18]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Single Ig IL-1-related receptor (SIGIRR).	[19]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Single Ig IL-1-related receptor (SIGIRR).	[20]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Single Ig IL-1-related receptor (SIGIRR).	[21]
Selenium	DM25CGV	Approved	Selenium increases the expression of Single Ig IL-1-related receptor (SIGIRR).	[22]
Obeticholic acid	DM3Q1SM	Approved	Obeticholic acid decreases the expression of Single Ig IL-1-related receptor (SIGIRR).	[23]
Diphenylpyraline	DMW4X37	Approved	Diphenylpyraline increases the expression of Single Ig IL-1-related receptor (SIGIRR).	[24]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Single Ig IL-1-related receptor (SIGIRR).	[25]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Single Ig IL-1-related receptor (SIGIRR).	[27]

References

• [1] Tuning inflammation and immunity by the negative regulators IL-1R2 and IL-1R8.Immunol Rev. 2018 Jan;281(1):233-247. doi: 10.1111/imr.12609.
• [2] Increased expression of IL-1R8 and a possible immunomodulatory role of its ligand IL-37 in allergic rhinitis patients.Int Immunopharmacol. 2018 Jul;60:152-159. doi: 10.1016/j.intimp.2018.04.002. Epub 2018 May 3.
• [3] IL-37 inhibits the maturation of dendritic cells through the IL-1R8-TLR4-NF-B pathway.Biochim Biophys Acta Mol Cell Biol Lipids. 2019 Oct;1864(10):1338-1349. doi: 10.1016/j.bbalip.2019.05.009. Epub 2019 May 21.
• [4] High IL-1R8 expression in breast tumors promotes tumor growth and contributes to impaired antitumor immunity.Oncotarget. 2017 Jul 25;8(30):49470-49483. doi: 10.18632/oncotarget.17713.
• [5] TNFAIP3, a negative regulator of the TLR signaling pathway, is a potential predictive biomarker of response to antidepressant treatment in major depressive disorder.Brain Behav Immun. 2017 Jan;59:265-272. doi: 10.1016/j.bbi.2016.09.014. Epub 2016 Sep 15.
• [6] The anti-inflammatory IL-37/SIGIRR axis is functionally compromised in HIV infection.AIDS. 2019 Sep 1;33(11):1693-1703. doi: 10.1097/QAD.0000000000002271.
• [7] The deubiquitinase USP13 stabilizes the anti-inflammatory receptor IL-1R8/Sigirr to suppress lung inflammation.EBioMedicine. 2019 Jul;45:553-562. doi: 10.1016/j.ebiom.2019.06.011. Epub 2019 Jun 14.
• [8] Revealed heterogeneity in rheumatoid arthritis based on multivariate innate signature analysis.Clin Exp Rheumatol. 2020 Mar-Apr;38(2):289-298. doi: 10.55563/clinexprheumatol/qb2ha3. Epub 2019 Aug 3.
• [9] Cross-Disease Innate Gene Signature: Emerging Diversity and Abundance in RA Comparing to SLE and SSc.J Immunol Res. 2019 Jul 16;2019:3575803. doi: 10.1155/2019/3575803. eCollection 2019.
• [10] Low Vitamin-D Levels Combined with PKP3-SIGIRR-TMEM16J Host Variants Is Associated with Tuberculosis and Death in HIV-Infected and -Exposed Infants.PLoS One. 2016 Feb 12;11(2):e0148649. doi: 10.1371/journal.pone.0148649. eCollection 2016.
• [11] IL-37 requires IL-18R and SIGIRR/IL-1R8 to diminish allergic airway inflammation in mice.Allergy. 2015 Apr;70(4):366-73. doi: 10.1111/all.12566. Epub 2015 Jan 26.
• [12] SIGIRR promotes resistance against Pseudomonas aeruginosa keratitis by down-regulating type-1 immunity and IL-1R1 and TLR4 signaling.J Immunol. 2006 Jul 1;177(1):548-56. doi: 10.4049/jimmunol.177.1.548.
• [13] Gene polymorphisms of Toll-like and related recognition receptors in relation to the vaginal carriage of Gardnerella vaginalis and Atopobium vaginae.J Reprod Immunol. 2009 Jan;79(2):163-73. doi: 10.1016/j.jri.2008.10.006. Epub 2009 Feb 6.
• [14] The inhibitory receptor toll interleukin-1R 8 (TIR8/IL-1R8/SIGIRR) is downregulated in chronic lymphocytic leukemia.Leuk Lymphoma. 2017 Oct;58(10):2419-2425. doi: 10.1080/10428194.2017.1295142. Epub 2017 Feb 28.
• [15] IL-1R8 is a checkpoint in NK cells regulating anti-tumour and anti-viral activity.Nature. 2017 Nov 2;551(7678):110-114. doi: 10.1038/nature24293. Epub 2017 Oct 25.
• [16] 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.
• [17] 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.
• [18] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [19] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [20] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [21] 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.
• [22] 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.
• [23] Pharmacotoxicology of clinically-relevant concentrations of obeticholic acid in an organotypic human hepatocyte system. Toxicol In Vitro. 2017 Mar;39:93-103.
• [24] Controlled diesel exhaust and allergen coexposure modulates microRNA and gene expression in humans: Effects on inflammatory lung markers. J Allergy Clin Immunol. 2016 Dec;138(6):1690-1700. doi: 10.1016/j.jaci.2016.02.038. Epub 2016 Apr 24.
• [25] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [26] 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.
• [27] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [28] 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.