User:Svarberb/SIGIRR

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 and immune response.

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 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 proliferation of Th17 lymphocytes. SIGIRR-deficient T lymphocytes lacks this negative regulation and it favours mTOR-dependent differentiation and proliferation of Th17 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.