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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 Inflammation (from ) is part of the biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. The five cardinal signs are heat, pain, redness, swelling, and loss of function (Latin ''calor'', '' ...
,
immune response An immune response is a physiological reaction which occurs within an organism in the context of inflammation for the purpose of defending against exogenous factors. These include a wide variety of different toxins, viruses, intra- and extracellula ...
, and
tumorigenesis Carcinogenesis, also called oncogenesis or tumorigenesis, is the formation of a cancer, whereby normal cells are transformed into cancer cells. The process is characterized by changes at the cellular, genetic, and epigenetic levels and abn ...
of
colonic Colon cleansing, also known as colon therapy, colon hydrotherapy, a colonic, or colonic irrigation, encompasses a number of alternative medical therapies claimed to remove toxins from the colon and intestinal tract by removing accumulations o ...
epithelial cells Epithelium or epithelial tissue is a thin, continuous, protective layer of cells with little extracellular matrix. An example is the epidermis, the outermost layer of the skin. Epithelial ( mesothelial) tissues line the outer surfaces of man ...
.


Gene

Human gene SIGIRR is localized on
chromosome A chromosome is a package of DNA containing part or all of the genetic material of an organism. In most chromosomes, the very long thin DNA fibers are coated with nucleosome-forming packaging proteins; in eukaryotic cells, the most import ...
11. It is composed of 10
exon An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequence ...
s spanning about 11,700 base pairs. In mice, this gene is on chromosome 7, where it is composed of 9 exons spanning about 9,400 base pairs.


Structure

SIGIRR is a 410
amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...
s long
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...
. 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 A transmembrane domain (TMD, TM domain) is a membrane-spanning protein domain. TMDs may consist of one or several alpha-helices or a transmembrane beta barrel. Because the interior of the lipid bilayer is hydrophobic, the amino acid residues in ...
, which is anchored to the plasmatic membrane. It has a TIR domain and 95
amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...
s 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 Protein tertiary structure is the three-dimensional shape of a protein. The tertiary structure will have a single polypeptide chain "backbone" with one or more protein secondary structures, the protein domains. Amino acid side chains and the ...
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. SIGIRR is extensively
glycosylated Glycosylation is the reaction in which a carbohydrate (or ' glycan'), i.e. a glycosyl donor, is attached to a hydroxyl or other functional group of another molecule (a glycosyl acceptor) in order to form a glycoconjugate. In biology (but not ...
on its extracellular domain, and loss of this modification impairs its function.


Expression

SIGIRR is expressed in several epithelial tissues, particularly in epithelial cells of
kidney In humans, the kidneys are two reddish-brown bean-shaped blood-filtering organ (anatomy), organs that are a multilobar, multipapillary form of mammalian kidneys, usually without signs of external lobulation. They are located on the left and rig ...
s,
digestive tract The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the Digestion, digestive system that leads from the mouth to the anus. The tract is the largest of the body's systems, after the cardiovascula ...
,
liver The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...
,
lung The lungs are the primary Organ (biology), organs of the respiratory system in many animals, including humans. In mammals and most other tetrapods, two lungs are located near the Vertebral column, backbone on either side of the heart. Their ...
s, and in lymphoid organs. It is also expressed in
monocyte Monocytes are a type of leukocyte or white blood cell. They are the largest type of leukocyte in blood and can differentiate into macrophages and monocyte-derived dendritic cells. As a part of the vertebrate innate immune system monocytes also ...
s,
B lymphocytes B cells, also known as B lymphocytes, are a type of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted or inserted into the plasm ...
,
T lymphocytes T cells (also known as T lymphocytes) are an important part of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes A lymphocyte is a type of white blood cell (leukoc ...
,
dendritic cell A dendritic cell (DC) is an antigen-presenting cell (also known as an ''accessory cell'') of the mammalian immune system. A DC's main function is to process antigen material and present it on the cell surface to the T cells of the immune system ...
s, and
NK cells Natural killer cells, also known as NK cells, are a type of cytotoxic lymphocyte critical to the innate immune system. They are a kind of large granular lymphocytes (LGL), and belong to the rapidly expanding family of known innate lymphoid cell ...
. In general, its expression is downregulated during
inflammation Inflammation (from ) is part of the biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. The five cardinal signs are heat, pain, redness, swelling, and loss of function (Latin ''calor'', '' ...
or
infection An infection is the invasion of tissue (biology), tissues by pathogens, their multiplication, and the reaction of host (biology), host tissues to the infectious agent and the toxins they produce. An infectious disease, also known as a transmis ...
. Its reduced expression was also found in patients with chronic lymphoid leukemia, 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 Glycosylation is the reaction in which a carbohydrate (or ' glycan'), i.e. a glycosyl donor, is attached to a hydroxyl or other functional group of another molecule (a glycosyl acceptor) in order to form a glycoconjugate. In biology (but not ...
of the
Wild type The wild type (WT) is the phenotype of the typical form of a species as it occurs in nature. Originally, the wild type was conceptualized as a product of the standard "normal" allele at a locus, in contrast to that produced by a non-standard, " ...
variant as its transported to the plasmatic membrane. One of the discovered
transcription factor In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription (genetics), transcription of genetics, genetic information from DNA to messenger RNA, by binding t ...
, 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 A mitogen-activated protein kinase (MAPK or MAP kinase) is a type of serine/threonine-specific protein kinases involved in directing cellular responses to a diverse array of stimuli, such as mitogens, osmotic stress, heat shock and proinflammato ...
, which is activated through the
TLR4 Toll-like receptor 4 (TLR4), also designated as CD284 (cluster of differentiation 284), is a key activator of the innate immune response and plays a central role in the fight against bacterial infections. TLR4 is a transmembrane protein of approx ...
signalization. Treatment of mice with a small amount of
lipopolysaccharide Lipopolysaccharide (LPS), now more commonly known as endotoxin, is a collective term for components of the outermost membrane of the cell envelope of gram-negative bacteria, such as '' E. coli'' and ''Salmonella'' with a common structural archit ...
, which is a ligand of
TLR4 Toll-like receptor 4 (TLR4), also designated as CD284 (cluster of differentiation 284), is a key activator of the innate immune response and plays a central role in the fight against bacterial infections. TLR4 is a transmembrane protein of approx ...
, this causes reduction in SIGIRR expression.


Function

SIGIRR negatively regulates the activation of the IL-1R1, IL18R1, IL-1R5/ST2,
TLR4 Toll-like receptor 4 (TLR4), also designated as CD284 (cluster of differentiation 284), is a key activator of the innate immune response and plays a central role in the fight against bacterial infections. TLR4 is a transmembrane protein of approx ...
,
TLR7 Toll-like receptor 7, also known as TLR7, is a protein that in humans is encoded by the ''TLR7'' gene. Orthologs are found in mammals and birds. It is a member of the toll-like receptor (TLR) family and detects single stranded RNA. Function T ...
,
TLR3 Toll-like receptor 3 (TLR3) also known as CD283 (cluster of differentiation 283) is a protein that in humans is encoded by the ''TLR3'' gene. TLR3 is a member of the toll-like receptor family of pattern recognition receptors of the innate immune ...
,
TLR9 Toll-like receptor 9 is a protein that in humans is encoded by the ''TLR9'' gene. TLR9 has also been designated as CD289 (cluster of differentiation 289). It is a member of the toll-like receptor (TLR) family. TLR9 is an important receptor expres ...
, and TLR1/2 and inhibits activation of transcription factor
NF-κB Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a family of transcription factor protein complexes that controls transcription (genetics), transcription of DNA, cytokine production and cell survival. NF-κB is found i ...
and
JNK c-Jun N-terminal kinases (JNKs), were originally identified as kinases that bind and phosphorylate c-Jun on Ser-63 and Ser-73 within its transcriptional activation domain. They belong to the mitogen-activated protein kinase family, and are r ...
MAP kinase A mitogen-activated protein kinase (MAPK or MAP kinase) is a type of serine/threonine-specific protein kinases involved in directing cellular responses to a diverse array of stimuli, such as mitogens, osmotic stress, heat shock and proinflammato ...
. SIGIRR interacts with IL-1R1 when it binds to IL-1. N terminal extracellular
immunoglobulin domain The immunoglobulin domain, also known as the immunoglobulin fold, is a type of protein domain that consists of a 2-layer sandwich of 7-9 antiparallel β-strands arranged in two β-sheets with a Greek key topology, consisting of about 125 amino ...
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. 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 The immunoglobulin domain, also known as the immunoglobulin fold, is a type of protein domain that consists of a 2-layer sandwich of 7-9 antiparallel β-strands arranged in two β-sheets with a Greek key topology, consisting of about 125 amino ...
of SIGIRR is dispensable for the inhibition of TLR4 signaling. 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 The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells ( intracellular fluid (ICF)). It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondri ...
. 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 Myeloid differentiation primary response 88 (MYD88) is a protein that, in humans, is encoded by the ''MYD88'' gene. originally discovered in the laboratory of Dan A. Liebermann (Lord et al. Oncogene 1990) as a Myeloid differentiation primary resp ...
, and it also prevents signalization through adaptor protein
TRIF TIR domain containing adaptor molecule 1 (TICAM1; formerly known as TIR-domain-containing adapter-inducing interferon-β or TRIF) is an adapter in responding to activation of toll-like receptors (TLRs). It mediates the rather delayed cascade of t ...
which is used, for example, by TLR3. Negative regulation of
IL-1R Interleukin-1 receptor (IL-1R) is a cytokine receptor which binds interleukin 1. Two forms of the receptor exist. The type I receptor is primarily responsible for transmitting the inflammatory effects of interleukin-1 (IL-1) while type II ...
pathway by SIGIRR has its effect on the differentiation of Th17 lymphocytes. IL-1 supports differentiation for Th17 lymphocytes and expression of
transcription factor In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription (genetics), transcription of genetics, genetic information from DNA to messenger RNA, by binding t ...
s RORγt and
IRF4 Interferon regulatory factor 4 (IRF4) also known as MUM1 is a protein that in humans is encoded by the ''IRF4'' gene. IRF4 functions as a key regulatory transcription factor in the development of human immune cells.Nam S, Lim J-S (2016). "Essentia ...
. Treatment by this
cytokine Cytokines () are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are produced by a broad range of cells, including immune cells like macrophages, B cell, B lymphocytes, T cell, T lymphocytes ...
also activates
mTOR The mammalian target of rapamycin (mTOR), also referred to as the mechanistic target of rapamycin, and sometimes called FK506-binding protein 12-rapamycin-associated protein 1 (FRAP1), is a kinase that in humans is encoded by the ''MTOR'' gene. ...
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. SIGIRR also negatively regulates TLRs, IL-1R pathway, and following mTOR activation in
intestinal epithelial cells The intestinal epithelium is the single cell layer that forms the luminal surface (lining) of both the small and large intestine (colon) of the gastrointestinal tract. Composed of simple columnar epithelium its main functions are absorptio ...
. Ligands for TLRs in the
intestine The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The tract is the largest of the body's systems, after the cardiovascular system. T ...
are mainly components of
intestinal microflora Gut microbiota, gut microbiome, or gut flora are the microorganisms, including bacteria, archaea, fungi, and viruses, that live in the digestive tracts of animals. The gastrointestinal metagenome is the aggregate of all the genomes of the gu ...
. Its deficiency or expression of mutated form in these cells leads to the signalization, which promotes
inflammation Inflammation (from ) is part of the biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. The five cardinal signs are heat, pain, redness, swelling, and loss of function (Latin ''calor'', '' ...
, proliferation and increases incidence of
tumors A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...
and its size.


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

SIGIRR takes part in mediating the anti-inflammatory
IL-37 Interleukin 37 (IL-37), also known as Interleukin-1 family member 7 (IL-1F7), is an anti-inflammatory cytokine important for the downregulation of pro-inflammatory cytokine production as well as the suppression of tumor cell growth. Gene locat ...
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 Proto-oncogene tyrosine-protein kinase Fyn (p59-FYN, Slk, Syn, MGC45350, Gene ID 2534) is an enzyme that in humans is encoded by the ''FYN'' gene. Fyn is a 59-kDa member of the Src family of kinases typically associated with T-cell and neurona ...
, p38,
JNK c-Jun N-terminal kinases (JNKs), were originally identified as kinases that bind and phosphorylate c-Jun on Ser-63 and Ser-73 within its transcriptional activation domain. They belong to the mitogen-activated protein kinase family, and are r ...
, ERK and it also causes activation of phosphatase PTEN, kinase MER, transcription factor
STAT3 Signal transducer and activator of transcription 3 (STAT3) is a transcription factor which in humans is encoded by the ''STAT3'' gene. It is a member of the STAT protein family. Function STAT3 is a member of the STAT protein family. In respon ...
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 An antibody (Ab) or immunoglobulin (Ig) is a large, Y-shaped protein belonging to the immunoglobulin superfamily which is used by the immune system to identify and neutralize antigens such as bacteria and viruses, including those that caus ...
. In addition to the regulation of inflammation, IL-37 also affects
metabolism Metabolism (, from ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cellular processes; the co ...
. 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 Oxidative phosphorylation(UK , US : or electron transport-linked phosphorylation or terminal oxidation, is the metabolic pathway in which Cell (biology), cells use enzymes to Redox, oxidize nutrients, thereby releasing chemical energy in order ...
,
Krebs cycle The citric acid cycle—also known as the Krebs cycle, Szent–Györgyi–Krebs cycle, or TCA cycle (tricarboxylic acid cycle)—is a series of biochemical reactions that release the energy stored in nutrients through acetyl-CoA oxidation. The e ...
,
nucleotide Nucleotides are Organic compound, organic molecules composed of a nitrogenous base, a pentose sugar and a phosphate. They serve as monomeric units of the nucleic acid polymers – deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), both o ...
, amino acids metabolism, and decrease of inflammatory mediators levels. This response does not occur in case of SIGIRR deficiency


References


Further reading

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