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SIGIRR
Identifiers
Aliases	SIGIRR, TIR8, single immunoglobulin and toll-interleukin 1 receptor (TIR) domain, IL-1R8, single Ig and TIR domain containing
External IDs	OMIM: 605478; MGI: 1344402; HomoloGene: 36399; GeneCards: SIGIRR; OMA:SIGIRR - orthologs
Gene location (Human) Chr. Chromosome 11 (human) Band 11p15.5 Start 405,716 bp End 417,455 bp
Gene location (Mouse) Chr. Chromosome 7 (mouse) Band 7|7 F5 Start 140,671,088 bp End 140,680,485 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in granulocyte mucosa of transverse colon right lobe of liver right uterine tube apex of heart olfactory zone of nasal mucosa spleen body of stomach C1 segment left uterine tube Top expressed in yolk sac right kidney proximal tubule human kidney epithelium of small intestine thymus intestinal villus crypt of lieberkuhn of small intestine ileum submandibular gland More reference expression data BioGPS More reference expression data
Gene ontology Molecular function protein binding Cellular component integral component of membrane membrane plasma membrane Biological process negative regulation of cytokine-mediated signaling pathway acute-phase response negative regulation of DNA-binding transcription factor activity signal transduction negative regulation of lipopolysaccharide-mediated signaling pathway cellular response to cytokine stimulus Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 59307 24058 Ensembl ENSG00000185187 ENSMUSG00000025494 UniProt Q6IA17 Q9JLZ8 RefSeq (mRNA) NM_001135053 NM_001135054 NM_021805 NM_023059 NM_001355055 RefSeq (protein) NP_001128525 NP_001128526 NP_068577 NP_075546 NP_001341984 Location (UCSC) Chr 11: 0.41 – 0.42 Mb Chr 7: 140.67 – 140.68 Mb PubMed search
Wikidata
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Single Ig IL-1-related receptor (SIGIRR), also called Toll/Interleukin-1 receptor 8 (TIR8) or Interleukin-1 receptor 8 (IL-1R8) is transmembrane protein encoded by gene SIGIRR, which modulate inflammation, immune response and tumorigenesis of colonic epithelial cells.

Gene

Human gene SIGIRR is localized on chromosome 11. It is composed of 10 exons spanning about 11 700 base pairs. In mouse this gene is on chromosome 7, where it is composed of 9 exons spanning about 9 400 base pairs.

Structure

SIGIRR is 410 amino acids long protein. In contrast with other members of IL-1 receptor family it has got only 1 immunoglobulin (Ig) domain in its N terminal extracellular part instead of 3 Ig domains. After this domain there is transmembrane domain, which is anchored plasmatic membrane. In intracellular part it has got TIR domain and 95 amino acid long C terminal tail, which is not present in other members of IL-1 receptor family. Structure of its TIR domain is different in case of SIGIRR. In its tertiary structure there are normally important amino acids Ser447 and Tyr536 replaced by amino acids Cys222 and Leu305. Functional Importance of these differences are not known so far. Human and mouse SIGIRR protein sequences are 82 % identical and they are overall 23 % identical with IL-1R1. SIGIRR is extensively glycosylated on its extracellular domain and loss of this modification impar its function.

Expression

SIGIRR is expressed in several epithelial tissue, particularly in epithelial cells of kidneys, digestive tract, liver, lungs and in lymphoid organs. It is also expressed in monocytes, B lymphocytes, T lymphocytes, dendritic cells and NK cells. In general, its expression is downregulated during inflammation or infection. Its reduced expression was also found in patients with chronic lymphoid leukemia. or in cells from colonic cancer. In human cells from colonic cancer, there was observed increased expression of one variant of SIGIRR. This variant lacks its exon 8, is not glycosylated and its function is impaired. It also inhibits glycosylation of Wild type variant a its transport to plasmatic membrane.

One of the discovered transcription factor, which regulate expression of SIGIRR, is SP1. It bind to the proximal part of promoter of the SIGIRR gene and induce its transcription. Binding of SP1 on SIGIRR promoter is inhibited by activation of p38 MAP kinase, which is activated through the TLR4 signalization. Treatment of mice with a small amount of lipopolysaccharide, which is ligand of TLR4, causes reduction in SIGIRR expression.

Function

SIGIRR negatively regulates the activation of the IL-1R1, IL18R1, IL-1R5/ST2, TLR4, TLR7, TLR3, TLR9, and TLR1/2 and inhibits activation of transcription factor NF-κB and JNK MAP kinase.

SIGIRR interacts with IL-1R1 when it binds IL-1. N terminal extracellular immunoglobulin domain associates with IL-1R1 and blocks its heterodimerization with IL-1RAP. In addition, C terminal TIR domain of SIGIRR binds downstream elements of IL-1R1 signalization and prevents constitution of functional signalling complex. Deletion of these domains disrupts regulation activity of SIGIRR. A little bit different mechanism is used by SIGIRR to regulate activity of TLR4. It also binds to receptor complex around TLR4. TIR domain of SIGIRR is crucial for interaction with TLR4 and it also interacts with downstream elements of TLR4 pathway. In contrast, extracellular immunoglobulin domain of SIGIRR is dispensable for inhibition of TLR4 signalling. There are 2 mechanisms, which are proposed for explanation of this inhibition of TLR4 pathway. First is that SIGIRR blocks formation of signalling complex at activated TLR4 and the second is that SIGIRR prevents translocation of this signalization complex into a cytosol.SIGIRR inhibits signal transduction by its interaction with TLRs, IL-1R1 and downstream signalling proteins and in this manner it participate in negative regulation of inflammation. SIGIRR also prevents homodimerization of MYD88 and it also prevents signalization through adaptor protein TRIF, which is used for example by TLR3.

Negative regulation of IL-1R pathway by SIGIRR has its effect on differentiation of T_h17 lymphocytes. IL-1 supports differentiation for T_h17 lymphocytes and expression of transcription factors RORγt and IRF4. Treatment by this cytokine also activates mTOR kinase and promotes proliferation of T_h17 lymphocytes. SIGIRR-deficient T lymphocytes lacks this negative regulation and it favours mTOR-dependent differentiation and proliferation of T_h17 lymphocytes.SIGIRR also negatively regulates TLRs, IL-1R pathway and following mTOR activation in intestinal epithelial cells. Ligands for TLRs in the intestine are mainly components of intestinal microflora. Its deficiency or expression of mutated form in these cells leads to the signalization, which promotes inflammation, proliferation and increases incidence of tumors and its size.

SIGIRR as a coreceptor of IL-1R5 for IL-37 binding

SIGIRR takes part in mediating of anti-inflammatory IL-37 signalization. It interacts with IL-37, IL-18R1 and forms tripartite signalling complex. Activity of this complex transduce anti-inflammatory signal and is essential for manifestation of IL-37 activity. Upon this signalization it causes inhibition of components of NF-κB pathway, kinases mTOR, TAK1, FYN, p38, JNK, ERK and it also causes activation of phosphatase PTEN, kinase MER, transcription factor STAT3 and adaptor protein p62 (DOK1). Pre-treatment of mice by IL-37 before injection reduced examined levels of pro-inflammatory cytokines and, also reduced their weight loss and hypothermia. This protective effect of IL-37 was abolished by deletion of SIGIRR, reduction of its expression or neutralization of IL-37 by antibodies.

In addition to regulation of inflammation, IL-37 also affects metabolism. Stimulation of skeletal muscle cells by IL-37 increases level of AMP-dependent kinase, increases it activation and induce metabolic reprogramming. It causes increase of oxidative phosphorylation, krebs cycle, nucleotide and amino acids metabolism and decrease of inflammatory mediators levels. This response does not occur in case of SIGIRR deficiency.

References

1. ^ GRCh38: Ensembl release 89: ENSG00000185187 – Ensembl, May 2017
2. ^ GRCm38: Ensembl release 89: ENSMUSG00000025494 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. ^ Molgora, Martina; Supino, Domenico; Mantovani, Alberto; Garlanda, Cecilia (2018). "Tuning inflammation and immunity by the negative regulators IL-1R2 and IL-1R8". Immunological Reviews. 281 (1): 233–247. doi:10.1111/imr.12609. ISSN 1600-065X. PMC 5922415. PMID 29247989.{{cite journal}}: CS1 maint: PMC format (link)
6. ^ Thomassen, Elisabeth; Renshaw, Blair R.; Sims, John E. (1999-06-01). "Identification and characterization of SIGIRR, a molecule representing a novel subtype of the IL-1R superfamily". Cytokine. 11 (6): 389–399. doi:10.1006/cyto.1998.0452. ISSN 1043-4666.
7. "Sigirr single immunoglobulin and toll-interleukin 1 receptor (TIR) domain [Mus musculus (house mouse)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2021-01-24.
8. ^ Zhao, Junjie; Bulek, Katarzyna; Gulen, Muhammet F.; Zepp, Jarod A.; Karagkounis, Georgio; Martin, Bradley N.; Zhou, Hao; Yu, Minjia; Liu, Xiuli; Huang, Emina; Fox, Paul L. (December 2015). "Human Colon Tumors Express a Dominant-Negative Form of SIGIRR That Promotes Inflammation and Colitis-Associated Colon Cancer in Mice". Gastroenterology. 149 (7): 1860–1871.e8. doi:10.1053/j.gastro.2015.08.051. ISSN 0016-5085. PMC 5308447. PMID 26344057.{{cite journal}}: CS1 maint: PMC format (link)
9. Vilia, Maria Giovanna; Fonte, Eleonora; Veliz Rodriguez, Tania; Tocchetti, Marta; Ranghetti, Pamela; Scarfò, Lydia; Papakonstantinou, Nikos; Ntoufa, Stavroula; Stamatopoulos, Kostas; Ghia, Paolo; Muzio, Marta (2017-10-03). "The inhibitory receptor toll interleukin-1R 8 (TIR8/IL-1R8/SIGIRR) is downregulated in chronic lymphocytic leukemia". Leukemia & Lymphoma. 58 (10): 2419–2425. doi:10.1080/10428194.2017.1295142. ISSN 1042-8194.
10. ^ Kadota, C.; Ishihara, S.; Aziz, M. M.; Rumi, M. A.; Oshima, N.; Mishima, Y.; Moriyama, I.; Yuki, T.; Amano, Y.; Kinoshita, Y. (2010). "Down-regulation of single immunoglobulin interleukin-1R-related molecule (SIGIRR)/TIR8 expression in intestinal epithelial cells during inflammation". Clinical & Experimental Immunology. 162 (2): 348–361. doi:10.1111/j.1365-2249.2010.04254.x. ISSN 1365-2249. PMC 2996602. PMID 21077278.{{cite journal}}: CS1 maint: PMC format (link)
11. Ueno-Shuto, Keiko; Kato, Kosuke; Tasaki, Yukihiro; Sato, Miki; Sato, Keizo; Uchida, Yuji; Sakai, Hiromichi; Ono, Tomomi; Suico, Mary Ann; Mitsutake, Kazunori; Tokutomi, Naofumi (June 2014). "Lipopolysaccharide Decreases Single Immunoglobulin Interleukin-1 Receptor-related Molecule (SIGIRR) Expression by Suppressing Specificity Protein 1 (Sp1) via the Toll-like Receptor 4 (TLR4)-p38 Pathway in Monocytes and Neutrophils". Journal of Biological Chemistry. 289 (26): 18097–18109. doi:10.1074/jbc.m113.532093. ISSN 0021-9258. PMC 4140261. PMID 24821721.{{cite journal}}: CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link)
12. ^ Qin, Jinzhong; Qian, Youcun; Yao, Jianhong; Grace, Cui; Li, Xiaoxia (2005-05-02). "SIGIRR Inhibits Interleukin-1 Receptor- and Toll-like Receptor 4-mediated Signaling through Different Mechanisms". Journal of Biological Chemistry. 280 (26): 25233–25241. doi:10.1074/jbc.m501363200. ISSN 0021-9258.{{cite journal}}: CS1 maint: unflagged free DOI (link)
13. ^ Wald, David; Qin, Jinzhong; Zhao, Zhendong; Qian, Youcun; Naramura, Mayumi; Tian, Liping; Towne, Jennifer; Sims, John E.; Stark, George R.; Li, Xiaoxia (September 2003). "SIGIRR, a negative regulator of Toll-like receptor–interleukin 1 receptor signaling". Nature Immunology. 4 (9): 920–927. doi:10.1038/ni968. ISSN 1529-2916.
14. ^ Guven-Maiorov, Emine; Keskin, Ozlem; Gursoy, Attila; Nussinov, Ruth (2015-09-15). "A Structural View of Negative Regulation of the Toll-like Receptor-Mediated Inflammatory Pathway". Biophysical Journal. 109 (6): 1214–1226. doi:10.1016/j.bpj.2015.06.048. ISSN 0006-3495. PMC 4576153. PMID 26276688.{{cite journal}}: CS1 maint: PMC format (link)
15. Gong, Jing; Wei, Tiandi; Stark, Robert W.; Jamitzky, Ferdinand; Heckl, Wolfgang M.; Anders, Hans J.; Lech, Maciej; Rössle, Shaila C. (2010-03-01). "Inhibition of Toll-like receptors TLR4 and 7 signaling pathways by SIGIRR: A computational approach". Journal of Structural Biology. 169 (3): 323–330. doi:10.1016/j.jsb.2009.12.007. ISSN 1047-8477.
16. Gulen, Muhammet F.; Kang, Zizhen; Bulek, Katarzyna; Youzhong, Wan; Kim, Tae Whan; Chen, Yi; Altuntas, Cengiz Z.; Sass Bak-Jensen, Kristian; McGeachy, Mandy J.; Do, Jeong-Su; Xiao, Hui (January 2010). "The Receptor SIGIRR Suppresses Th17 Cell Proliferation via Inhibition of the Interleukin-1 Receptor Pathway and mTOR Kinase Activation". Immunity. 32 (1): 54–66. doi:10.1016/j.immuni.2009.12.003. ISSN 1074-7613. PMC 3015141. PMID 20060329.{{cite journal}}: CS1 maint: PMC format (link)
17. Xiao, Hui; Yin, Weiguo; Khan, Mohammed A.; Gulen, Muhammet F.; Zhou, Hang; Sham, Ho Pan; Jacobson, Kevan; Vallance, Bruce A.; Li, Xiaoxia (August 2010). "Loss of Single Immunoglobulin Interlukin-1 Receptor-Related Molecule Leads to Enhanced Colonic Polyposis in Apcmin Mice". Gastroenterology. 139 (2): 574–585. doi:10.1053/j.gastro.2010.04.043. PMC 3261756. PMID 20416302.{{cite journal}}: CS1 maint: PMC format (link)
18. Nold-Petry, Claudia A.; Lo, Camden Y.; Rudloff, Ina; Elgass, Kirstin D.; Li, Suzhao; Gantier, Michael P.; Lotz-Havla, Amelie S.; Gersting, Søren W.; Cho, Steven X.; Lao, Jason C.; Ellisdon, Andrew M. (April 2015). "IL-37 requires the receptors IL-18Rα and IL-1R8 (SIGIRR) to carry out its multifaceted anti-inflammatory program upon innate signal transduction". Nature Immunology. 16 (4): 354–365. doi:10.1038/ni.3103. ISSN 1529-2916.
19. Li, Suzhao; Neff, C. Preston; Barber, Kristina; Hong, Jaewoo; Luo, Yuchun; Azam, Tania; Palmer, Brent E.; Fujita, Mayumi; Garlanda, Cecilia; Mantovani, Alberto; Kim, Soohyun (2015-02-05). "Extracellular forms of IL-37 inhibit innate inflammation in vitro and in vivo but require the IL-1 family decoy receptor IL-1R8". Proceedings of the National Academy of Sciences. 112 (8): 2497–2502. doi:10.1073/pnas.1424626112. ISSN 0027-8424. PMC 4345608. PMID 25654981.{{cite journal}}: CS1 maint: PMC format (link)
20. Cavalli, Giulio; Justice, Jamie N.; Boyle, Kristen E.; D’Alessandro, Angelo; Eisenmesser, Elan Z.; Herrera, Jonathan J.; Hansen, Kirk C.; Nemkov, Travis; Stienstra, Rinke; Garlanda, Cecilia; Mantovani, Alberto (2017-02-28). "Interleukin 37 reverses the metabolic cost of inflammation, increases oxidative respiration, and improves exercise tolerance". Proceedings of the National Academy of Sciences. 114 (9): 2313–2318. doi:10.1073/pnas.1619011114. ISSN 0027-8424. PMC 5338542. PMID 28193888.{{cite journal}}: CS1 maint: PMC format (link)

Further reading

• Du X, Poltorak A, Wei Y, Beutler B (2000). "Three novel mammalian toll-like receptors: gene structure, expression, and evolution". Eur. Cytokine Netw. 11 (3): 362–71. PMID 11022119.
• Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.
• Clark HF, Gurney AL, Abaya E, et al. (2003). "The secreted protein discovery initiative (SPDI), a large-scale effort to identify novel human secreted and transmembrane proteins: a bioinformatics assessment". Genome Res. 13 (10): 2265–70. doi:10.1101/gr.1293003. PMC 403697. PMID 12975309.
• Ota T, Suzuki Y, Nishikawa T, et al. (2004). "Complete sequencing and characterization of 21,243 full-length human cDNAs". Nat. Genet. 36 (1): 40–5. doi:10.1038/ng1285. PMID 14702039.
• Polentarutti N, Rol GP, Muzio M, et al. (2004). "Unique pattern of expression and inhibition of IL-1 signaling by the IL-1 receptor family member TIR8/SIGIRR". Eur. Cytokine Netw. 14 (4): 211–8. PMID 14715412.
• Gerhard DS, Wagner L, Feingold EA, et al. (2004). "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)". Genome Res. 14 (10B): 2121–7. doi:10.1101/gr.2596504. PMC 528928. PMID 15489334.
• Qin J, Qian Y, Yao J, et al. (2005). "SIGIRR inhibits interleukin-1 receptor- and toll-like receptor 4-mediated signaling through different mechanisms". J. Biol. Chem. 280 (26): 25233–41. doi:10.1074/jbc.M501363200. PMID 15866876.

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