SIGIRR

Last updated
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
Orthologs
SpeciesHumanMouse
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 [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

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. [5]

Contents

Gene

Human gene SIGIRR is localized on chromosome 11. It is composed of 10 exons spanning about 11,700 base pairs. [6] In mice, this gene is on chromosome 7, where it is composed of 9 exons spanning about 9,400 base pairs. [7]

Structure

SIGIRR is a 410 amino acids long protein. In contrast with other members of IL-1 receptor family it has only 1 immunoglobulin (Ig) domain in its N terminal extracellular part instead of 3 Ig domains. After this domain, there is a transmembrane domain, which is anchored to the plasmatic membrane. It has a TIR domain and 95 amino acids long C terminal tail in the intracellular part, which is not present in other IL-1 receptor family members. Structure of the TIR domain is different in the case of SIGIRR. In its tertiary structure SIGIRR lacks amino acids Ser447 and Tyr536, which are important for IL-1R1 signalization. Instead of these amino acids SIGIRR contains Cys222 and Leu305. The functional importance of these differences is not known so far. Human and mouse SIGIRR protein sequences are 82% identical, and they are overall 23% identical with IL-1R1. [5] [6] SIGIRR is extensively glycosylated on its extracellular domain, and loss of this modification impairs its function. [8]

Expression

SIGIRR is expressed in several epithelial tissues, particularly in epithelial cells of kidneys, digestive tract, liver, lungs, and in lymphoid organs. [6] 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. [5] Its reduced expression was also found in patients with chronic lymphoid leukemia, [9] or in cells from colonic cancer. In human cells from colonic cancer, it was observed that there was an 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 the Wild type variant as its transported to the plasmatic membrane. [8]

One of the discovered transcription factor, which regulates the expression of SIGIRR, is SP1. It binds to the proximal part of the promoter of the SIGIRR gene and induce its transcription. Binding of SP1 on SIGIRR promoter is inhibited by the activation of p38 MAP kinase, which is activated through the TLR4 signalization. Treatment of mice with a small amount of lipopolysaccharide, which is a ligand of TLR4, this causes reduction in SIGIRR expression. [10] [11]

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. [5]

SIGIRR interacts with IL-1R1 when it binds to 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 the constitution of the functional signaling complex. Deletion of these domains disrupts the regulation activity of SIGIRR. [12] [13] SIGIRR uses a slightly different mechanism to regulate the activity of TLR4 by binding to the receptor complex around TLR4. TIR domain of SIGIRR is crucial for interaction with TLR4, and it also interacts with downstream elements of the TLR4 pathway. In contrast, the extracellular immunoglobulin domain of SIGIRR is dispensable for the inhibition of TLR4 signaling. [12] There are 2 mechanisms, which are proposed for explanation of the inhibition of the TLR4 pathway. First is that SIGIRR blocks the formation of signaling complex at activated TLR4 and the second is that SIGIRR prevents translocation of this signalization complex into a cytosol. [13] [14] SIGIRR inhibits signal transduction by its interaction with TLRs, IL-1R1 and downstream signaling proteins, and in this manner, it participates in negative regulation of inflammation. SIGIRR also prevents homodimerization of MYD88, [15] and it also prevents signalization through adaptor protein TRIF which is used, for example, by TLR3. [14]

Negative regulation of IL-1R pathway by SIGIRR has its effect on the differentiation of Th17 lymphocytes. IL-1 supports differentiation for Th17 lymphocytes and expression of transcription factors RORγt and IRF4. Treatment by this cytokine also activates mTOR kinase and promotes the proliferation of Th17 lymphocytes. SIGIRR-deficient T lymphocytes lack this negative regulation, and it favors mTOR-dependent differentiation and proliferation of Th17 lymphocytes. [16] 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. [8] [17] [10]

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

SIGIRR takes part in mediating the anti-inflammatory IL-37 signalization. It interacts with IL-37, IL-18R1 and forms tripartite signaling 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 of lipopolysaccharide 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. [18] [19]

In addition to the regulation of inflammation, IL-37 also affects metabolism. Stimulation of skeletal muscle cells by IL-37 increases level of AMP-dependent kinase, increases its activation and induces metabolic reprogramming. It causes increase of oxidative phosphorylation, Krebs cycle, nucleotide, amino acids metabolism, and decrease of inflammatory mediators levels. This response does not occur in case of SIGIRR deficiency [20]

Related Research Articles

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Toll-like receptors (TLRs) are a class of proteins that play a key role in the innate immune system. They are single-spanning receptors usually expressed on sentinel cells such as macrophages and dendritic cells, that recognize structurally conserved molecules derived from microbes. Once these microbes have reached physical barriers such as the skin or intestinal tract mucosa, they are recognized by TLRs, which activate immune cell responses. The TLRs include TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR11, TLR12, and TLR13. Humans lack genes for TLR11, TLR12 and TLR13 and mice lack a functional gene for TLR10. The receptors TLR1, TLR2, TLR4, TLR5, TLR6, and TLR10 are located on the cell membrane, whereas TLR3, TLR7, TLR8, and TLR9 are located in intracellular vesicles.

<span class="mw-page-title-main">IRAK4</span> Protein-coding gene in humans

IRAK-4, in the IRAK family, is a protein kinase involved in signaling innate immune responses from Toll-like receptors. It also supports signaling from T-cell receptors. IRAK4 contains domain structures which are similar to those of IRAK1, IRAK2, IRAKM and Pelle. IRAK4 is unique compared to IRAK1, IRAK2 and IRAKM in that it functions upstream of the other IRAKs, but is more similar to Pelle in this trait. IRAK4 has important clinical applications.

<span class="mw-page-title-main">MYD88</span> Protein-coding gene in the species Homo sapiens

Myeloid differentiation primary response 88 (MYD88) is a protein that, in humans, is encoded by the MYD88 gene.

<span class="mw-page-title-main">Interleukin 18</span> Protein-coding gene in the species Homo sapiens

Interleukin-18 (IL-18), also known as interferon-gamma inducing factor is a protein which in humans is encoded by the IL18 gene. The protein encoded by this gene is a proinflammatory cytokine. Many cell types, both hematopoietic cells and non-hematopoietic cells, have the potential to produce IL-18. It was first described in 1989 as a factor that induced interferon-γ (IFN-γ) production in mouse spleen cells. Originally, IL-18 production was recognized in Kupffer cells, liver-resident macrophages. However, IL-18 is constitutively expressed in non-hematopoietic cells, such as intestinal epithelial cells, keratinocytes, and endothelial cells. IL-18 can modulate both innate and adaptive immunity and its dysregulation can cause autoimmune or inflammatory diseases.

<span class="mw-page-title-main">Interleukin 26</span>

Interleukin-26 (IL-26) is a protein that in humans is encoded by the IL26 gene.

<span class="mw-page-title-main">Interleukin 17</span> Group of proteins

Interleukin 17 family is a family of pro-inflammatory cystine knot cytokines. They are produced by a group of T helper cell known as T helper 17 cell in response to their stimulation with IL-23. Originally, Th17 was identified in 1993 by Rouvier et al. who isolated IL17A transcript from a rodent T-cell hybridoma. The protein encoded by IL17A is a founding member of IL-17 family. IL17A protein exhibits a high homology with a viral IL-17-like protein encoded in the genome of T-lymphotropic rhadinovirus Herpesvirus saimiri. In rodents, IL-17A is often referred to as CTLA8.

<span class="mw-page-title-main">Toll-like receptor 4</span> Protein-coding gene in the species Homo sapiens

Toll-like receptor 4 is a protein that in humans is encoded by the TLR4 gene. TLR4 is a transmembrane protein, member of the toll-like receptor family, which belongs to the pattern recognition receptor (PRR) family. Its activation leads to an intracellular signaling pathway NF-κB and inflammatory cytokine production which is responsible for activating the innate immune system.

<span class="mw-page-title-main">IRAK1</span> Protein-coding gene in the species Homo sapiens

Interleukin-1 receptor-associated kinase 1 (IRAK-1) is an enzyme in humans encoded by the IRAK1 gene. IRAK-1 plays an important role in the regulation of the expression of inflammatory genes by immune cells, such as monocytes and macrophages, which in turn help the immune system in eliminating bacteria, viruses, and other pathogens. IRAK-1 is part of the IRAK family consisting of IRAK-1, IRAK-2, IRAK-3, and IRAK-4, and is activated by inflammatory molecules released by signaling pathways during pathogenic attack. IRAK-1 is classified as a kinase enzyme, which regulates pathways in both innate and adaptive immune systems.

<span class="mw-page-title-main">TEC (gene)</span> Human gene

Tyrosine-protein kinase Tec is a tyrosine kinase that in humans is encoded by the TEC gene. Tec kinase is expressed in hematopoietic, liver, and kidney cells and plays an important role in T-helper cell processes. Tec kinase is the name-giving member of the Tec kinase family, a family of non-receptor protein-tyrosine kinases.

<span class="mw-page-title-main">IL18R1</span> Protein-coding gene in the species Homo sapiens

The interleukin-18 receptor 1 (IL-18R1) is an interleukin receptor of the immunoglobulin superfamily. IL18R1 is its human gene. IL18R1 is also known as CDw218a.

<span class="mw-page-title-main">Interleukin-17A</span> Protein-coding gene in the species Homo sapiens

Interleukin-17A is a protein that in humans is encoded by the IL17A gene. In rodents, IL-17A used to be referred to as CTLA8, after the similarity with a viral gene.

<span class="mw-page-title-main">IL2RA</span> Mammalian protein found in Homo sapiens

The Interleukin-2 receptor alpha chain is a protein involved in the assembly of the high-affinity Interleukin-2 receptor, consisting of alpha (IL2RA), beta (IL2RB) and the common gamma chain (IL2RG). As the name indicates, this receptor interacts with Interleukin-2, a pleiotropic cytokine which plays an important role in immune homeostasis.

<span class="mw-page-title-main">Toll-interleukin receptor</span>

The toll-interleukin-1 receptor (TIR) homology domain is an intracellular signaling domain found in MyD88, SARM1, interleukin-1 receptors, toll receptors and many plant R proteins. It contains three highly conserved regions, and mediates protein-protein interactions between the toll-like receptors (TLRs) and signal-transduction components. TIR-like motifs are also found in plant proteins where they are involved in resistance to disease and in bacteria where they are associated with virulence. When activated, TIR domains recruit cytoplasmic adaptor proteins MyD88 (UniProt Q99836) and TOLLIP (toll-interacting protein, UniProt Q9H0E2). In turn, these associate with various kinases to set off signaling cascades. Some TIR domains have also been found to have intrinsic NAD+ cleavage activity, such as in SARM1. In the case of SARM1, the TIR NADase activity leads to the production of Nam, ADPR and cADPR and the activation of downstream pathways involved in Wallerian degeneration and neuron death.

<span class="mw-page-title-main">Interleukin-1 family</span> Group of cytokines playing a key role in the regulation of immune and inflammatory responses

The Interleukin-1 family is a group of 11 cytokines that plays a central role in the regulation of immune and inflammatory responses to infections or sterile insults.

<span class="mw-page-title-main">IL1RL1</span> Protein-coding gene in the species Homo sapiens

Interleukin 1 receptor-like 1, also known as IL1RL1 and ST2, is a protein that in humans is encoded by the IL1RL1 gene.

Members of the very wide interleukin-1 receptor (IL-1R) family are characterized by extracellular immunoglobulin-like domains and intracellular Toll/Interleukin-1R (TIR) domain. It is a group of structurally homologous proteins, conserved throughout the species as it was identified from plants to mammals. Proteins of this family play important role in host defence, injury and stress. There are four main groups of TIR domain-containing proteins in animals; Toll-like receptors, Interleukin-1 receptor (IL-1R), cytosolic adaptor proteins and insect and nematode Toll. Each of these groups is involved mainly in host defence; Toll receptors are also involved in embryogenesis.

<span class="mw-page-title-main">Interleukin 23</span> Heterodimeric cytokine acting as mediator of inflammation

Interleukin 23 (IL-23) is a heterodimeric cytokine composed of an IL-12B (IL-12p40) subunit and an IL-23A (IL-23p19) subunit. IL-23 is part of the IL-12 family of cytokines. The functional receptor for IL-23 consists of a heterodimer between IL-12Rβ1 and IL-23R.

The interleukin-1 receptor (IL-1R) associated kinase (IRAK) family plays a crucial role in the protective response to pathogens introduced into the human body by inducing acute inflammation followed by additional adaptive immune responses. IRAKs are essential components of the Interleukin-1 receptor signaling pathway and some Toll-like receptor signaling pathways. Toll-like receptors (TLRs) detect microorganisms by recognizing specific pathogen-associated molecular patterns (PAMPs) and IL-1R family members respond the interleukin-1 (IL-1) family cytokines. These receptors initiate an intracellular signaling cascade through adaptor proteins, primarily, MyD88. This is followed by the activation of IRAKs. TLRs and IL-1R members have a highly conserved amino acid sequence in their cytoplasmic domain called the Toll/Interleukin-1 (TIR) domain. The elicitation of different TLRs/IL-1Rs results in similar signaling cascades due to their homologous TIR motif leading to the activation of mitogen-activated protein kinases (MAPKs) and the IκB kinase (IKK) complex, which initiates a nuclear factor-κB (NF-κB) and AP-1-dependent transcriptional response of pro-inflammatory genes. Understanding the key players and their roles in the TLR/IL-1R pathway is important because the presence of mutations causing the abnormal regulation of Toll/IL-1R signaling leading to a variety of acute inflammatory and autoimmune diseases.

<span class="mw-page-title-main">IL17RD</span>

Interleukin 17 receptor D is a protein that in humans is encoded by the IL17RD gene.

<span class="mw-page-title-main">Interleukin 17F</span>

Interleukin 17F (IL-17F) is signaling protein that is in human is encoded by the IL17F gene and is considered a pro-inflammatory cytokine. This protein belongs to the interleukin 17 family and is mainly produced by the T helper 17 cells after their stimulation with interleukin 23. However, IL-17F can be also produced by a wide range of cell types, including innate immune cells and epithelial cells.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000185187 - Ensembl, May 2017
  2. 1 2 3 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. 1 2 3 4 Molgora M, Supino D, Mantovani A, Garlanda C (January 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. PMC   5922415 . PMID   29247989.
  6. 1 2 3 Thomassen E, Renshaw BR, Sims JE (June 1999). "Identification and characterization of SIGIRR, a molecule representing a novel subtype of the IL-1R superfamily". Cytokine. 11 (6): 389–99. doi:10.1006/cyto.1998.0452. PMID   10346978.
  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. 1 2 3 Zhao J, Bulek K, Gulen MF, Zepp JA, Karagkounis G, Martin BN, et al. (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. PMC   5308447 . PMID   26344057.
  9. ↑ Vilia MG, Fonte E, Veliz Rodriguez T, Tocchetti M, Ranghetti P, Scarfò L, et al. (October 2017). "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. PMID   28278705. S2CID   11804905.
  10. 1 2 Kadota C, Ishihara S, Aziz MM, Rumi MA, Oshima N, Mishima Y, et al. (November 2010). "Down-regulation of single immunoglobulin interleukin-1R-related molecule (SIGIRR)/TIR8 expression in intestinal epithelial cells during inflammation". Clinical and Experimental Immunology. 162 (2): 348–61. doi:10.1111/j.1365-2249.2010.04254.x. PMC   2996602 . PMID   21077278.
  11. ↑ Ueno-Shuto K, Kato K, Tasaki Y, Sato M, Sato K, Uchida Y, et al. (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". The Journal of Biological Chemistry. 289 (26): 18097–109. doi: 10.1074/jbc.m113.532093 . PMC   4140261 . PMID   24821721.
  12. 1 2 Qin J, Qian Y, Yao J, Grace C, Li X (July 2005). "SIGIRR inhibits interleukin-1 receptor- and toll-like receptor 4-mediated signaling through different mechanisms". The Journal of Biological Chemistry. 280 (26): 25233–41. doi: 10.1074/jbc.m501363200 . PMID   15866876.
  13. 1 2 Wald D, Qin J, Zhao Z, Qian Y, Naramura M, Tian L, et al. (September 2003). "SIGIRR, a negative regulator of Toll-like receptor-interleukin 1 receptor signaling". Nature Immunology. 4 (9): 920–7. doi:10.1038/ni968. PMID   12925853. S2CID   25246605.
  14. 1 2 Guven-Maiorov E, Keskin O, Gursoy A, Nussinov R (September 2015). "A Structural View of Negative Regulation of the Toll-like Receptor-Mediated Inflammatory Pathway". Biophysical Journal. 109 (6): 1214–26. Bibcode:2015BpJ...109.1214G. doi:10.1016/j.bpj.2015.06.048. PMC   4576153 . PMID   26276688.
  15. ↑ Gong J, Wei T, Stark RW, Jamitzky F, Heckl WM, Anders HJ, et al. (March 2010). "Inhibition of Toll-like receptors TLR4 and 7 signaling pathways by SIGIRR: a computational approach". Journal of Structural Biology. 169 (3): 323–30. doi:10.1016/j.jsb.2009.12.007. PMID   20025973.
  16. ↑ Gulen MF, Kang Z, Bulek K, Youzhong W, Kim TW, Chen Y, et al. (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. PMC   3015141 . PMID   20060329.
  17. ↑ Xiao H, Yin W, Khan MA, Gulen MF, Zhou H, Sham HP, et al. (August 2010). "Loss of single immunoglobulin interlukin-1 receptor-related molecule leads to enhanced colonic polyposis in Apc(min) mice". Gastroenterology. 139 (2): 574–85. doi:10.1053/j.gastro.2010.04.043. PMC   3261756 . PMID   20416302.
  18. ↑ Nold-Petry CA, Lo CY, Rudloff I, Elgass KD, Li S, Gantier MP, et al. (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): 354–65. doi:10.1038/ni.3103. PMID   25729923. S2CID   24578661.
  19. ↑ Li S, Neff CP, Barber K, Hong J, Luo Y, Azam T, et al. (February 2015). "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 of the United States of America. 112 (8): 2497–502. Bibcode:2015PNAS..112.2497L. doi: 10.1073/pnas.1424626112 . PMC   4345608 . PMID   25654981.
  20. ↑ Cavalli G, Justice JN, Boyle KE, D'Alessandro A, Eisenmesser EZ, Herrera JJ, et al. (February 2017). "Interleukin 37 reverses the metabolic cost of inflammation, increases oxidative respiration, and improves exercise tolerance". Proceedings of the National Academy of Sciences of the United States of America. 114 (9): 2313–2318. Bibcode:2017PNAS..114.2313C. doi: 10.1073/pnas.1619011114 . PMC   5338542 . PMID   28193888.

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