TCIRG1
Encyclopedia
V-type proton ATPase 116 kDa subunit a isoform 3 is an enzyme
that in humans is encoded by the TCIRG1 gene
.
, this gene encodes two protein isoforms with similarity to subunits of the vacuolar
ATPase (V-ATPase
) but the encoded proteins seem to have different functions. V-ATPase is a multisubunit enzyme that mediates acidification of eukaryotic intracellular organelles. V-ATPase dependent organelle acidification is necessary for such intracellular processes as protein sorting, zymogen
activation, and receptor-mediated endocytosis
. V-ATPase is composed of a cytosolic V1 domain and a transmembrane V0 domain.
The two isoforms are:
TIRC7 is expressed in T lymphocytes and is essential for normal T cell activation. This variant uses a transcription
start site that is within exon
5 of variant 1 followed by an intron
as part of its 5' UTR.
protein
induced after immune activation on the cell surface of certain peripheral human T and B cell
s as well as monocyte
s and IL-10 expressing regulatory T cell
s. During immune activation, TIRC7 is co-localized with the T cell receptor
and CTLA4 within the immune synapse of human T cell
s At the protein and mRNA level, its expression
is induced in lymphocytes in synovial
tissues obtained from patients with rheumatoid arthritis
or during rejection of solid organ transplants and bone marrow
transplantation as well as in brain
tissues obtained from patients with multiple sclerosis
.
targeting of TIRC7 reveals significant prevention of inflammation
in variety of animal model
s e.g. rejection
of transplanted kidney and heart allografts as well as progression of arthritis and EAE. These therapeutic effects were accompanied with significant decreases of Th1 specific cytokine
s e.g. IFN-gamma, TNF-alpha, IL-2 expression and transcription, induction of CTLA4 whereas IL-10 remained unchanged. The induction of TIRC7 in IL-10 secreting T regulatory cells and the prevention of colitis in the presence of TIRC7 positive T regulatory cells supports the inhibitory signals induced via TIRC7 pathway during immune activation. Further evidence for the inhibitory role of TIRC7 during the course of immune response is that prevention of colitis
was achievable by a transfer of TIRC7 positive cells
into CD45RO mice prior to induction of colitis. The negative immune regulatory role of TIRC7 is furthermore supported by the fact that TIRC7 knock out mice exhibits an increased T and B cell response in the presence of various stimuli in vitro
and in vivo
exhibiting. A significant induced memory cell
subset and reduction of CTLA4 expression observed in TIRC7 knock out mice.
9, inhibition of lymphocyte proliferation, SHP-1 recruitment, decrease in phosphorylation
of STAT4
, TCR-ζ chain and ZAP70 as well as inhibition of FasL expression. HLA-DRα2 and TIRC7 co-localize at the APC-T cell interaction site. In vivo, triggering the HLA-DR-TIRC7 pathway in lipopolysaccaride (LPS
) activated lymphocytes using soluble HLA-DRα2 leads to inhibition of proinflammatory as well as inflammatory
cytokines and induction of apoptosis
. These results strongly support the regulatory role of TIRC7 signalling pathway in lymphocyte
s.
.
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
that in humans is encoded by the TCIRG1 gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
.
Function
Through alternate splicingRNA splicing
In molecular biology and genetics, splicing is a modification of an RNA after transcription, in which introns are removed and exons are joined. This is needed for the typical eukaryotic messenger RNA before it can be used to produce a correct protein through translation...
, this gene encodes two protein isoforms with similarity to subunits of the vacuolar
Vacuole
A vacuole is a membrane-bound organelle which is present in all plant and fungal cells and some protist, animal and bacterial cells. Vacuoles are essentially enclosed compartments which are filled with water containing inorganic and organic molecules including enzymes in solution, though in certain...
ATPase (V-ATPase
V-ATPase
Vacuolar-type H+-ATPase is a highly conserved evolutionarily ancient enzyme with remarkably diverse functions in eukaryotic organisms. V-ATPases acidify a wide array of intracellular organelles and pump protons across the plasma membranes of numerous cell types...
) but the encoded proteins seem to have different functions. V-ATPase is a multisubunit enzyme that mediates acidification of eukaryotic intracellular organelles. V-ATPase dependent organelle acidification is necessary for such intracellular processes as protein sorting, zymogen
Zymogen
A zymogen is an inactive enzyme precursor. A zymogen requires a biochemical change for it to become an active enzyme. The biochemical change usually occurs in a lysosome where a specific part of the precursor enzyme is cleaved in order to activate it...
activation, and receptor-mediated endocytosis
Endocytosis
Endocytosis is a process by which cells absorb molecules by engulfing them. It is used by all cells of the body because most substances important to them are large polar molecules that cannot pass through the hydrophobic plasma or cell membrane...
. V-ATPase is composed of a cytosolic V1 domain and a transmembrane V0 domain.
The two isoforms are:
- long isoform a, also named OC116
- short isoform b, also named TIRC7 (N-terminus truncated, lacks amino acid residues 1-216 of the long isoform)
TIRC7 is expressed in T lymphocytes and is essential for normal T cell activation. This variant uses a transcription
Transcription (genetics)
Transcription is the process of creating a complementary RNA copy of a sequence of DNA. Both RNA and DNA are nucleic acids, which use base pairs of nucleotides as a complementary language that can be converted back and forth from DNA to RNA by the action of the correct enzymes...
start site that is within exon
Exon
An exon is a nucleic acid sequence that is represented in the mature form of an RNA molecule either after portions of a precursor RNA have been removed by cis-splicing or when two or more precursor RNA molecules have been ligated by trans-splicing. The mature RNA molecule can be a messenger RNA...
5 of variant 1 followed by an intron
Intron
An intron is any nucleotide sequence within a gene that is removed by RNA splicing to generate the final mature RNA product of a gene. The term intron refers to both the DNA sequence within a gene, and the corresponding sequence in RNA transcripts. Sequences that are joined together in the final...
as part of its 5' UTR.
Expression
TIRC7 is a membraneBiological membrane
A biological membrane or biomembrane is an enclosing or separatingmembrane that acts as a selective barrier, within or around a cell. It consists of a lipid bilayer with embedded proteins that may constitute close to 50% of membrane content...
protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
induced after immune activation on the cell surface of certain peripheral human T and B cell
B cell
B cells are lymphocytes that play a large role in the humoral immune response . The principal functions of B cells are to make antibodies against antigens, perform the role of antigen-presenting cells and eventually develop into memory B cells after activation by antigen interaction...
s as well as monocyte
Monocyte
Monocytes are a type of white blood cell and are part of the innate immune system of vertebrates including all mammals , birds, reptiles, and fish. Monocytes play multiple roles in immune function...
s and IL-10 expressing regulatory T cell
Regulatory T cell
Regulatory T cells , sometimes known as suppressor T cells, are a specialized subpopulation of T cells which suppresses activation of the immune system and thereby maintains tolerance to self-antigens. The existence of regulatory T cells was the subject of significant controversy among...
s. During immune activation, TIRC7 is co-localized with the T cell receptor
T cell receptor
The T cell receptor or TCR is a molecule found on the surface of T lymphocytes that is responsible for recognizing antigens bound to major histocompatibility complex molecules...
and CTLA4 within the immune synapse of human T cell
T cell
T cells or T lymphocytes belong to a group of white blood cells known as lymphocytes, and play a central role in cell-mediated immunity. They can be distinguished from other lymphocytes, such as B cells and natural killer cells , by the presence of a T cell receptor on the cell surface. They are...
s At the protein and mRNA level, its expression
Gene expression
Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product. These products are often proteins, but in non-protein coding genes such as ribosomal RNA , transfer RNA or small nuclear RNA genes, the product is a functional RNA...
is induced in lymphocytes in synovial
Synovial
Synovial may refer to:* Synovial fluid* Synovial joint* Synovial membrane...
tissues obtained from patients with rheumatoid arthritis
Rheumatoid arthritis
Rheumatoid arthritis is a chronic, systemic inflammatory disorder that may affect many tissues and organs, but principally attacks synovial joints. The process produces an inflammatory response of the synovium secondary to hyperplasia of synovial cells, excess synovial fluid, and the development...
or during rejection of solid organ transplants and bone marrow
Bone marrow
Bone marrow is the flexible tissue found in the interior of bones. In humans, bone marrow in large bones produces new blood cells. On average, bone marrow constitutes 4% of the total body mass of humans; in adults weighing 65 kg , bone marrow accounts for approximately 2.6 kg...
transplantation as well as in brain
Brain
The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...
tissues obtained from patients with multiple sclerosis
Multiple sclerosis
Multiple sclerosis is an inflammatory disease in which the fatty myelin sheaths around the axons of the brain and spinal cord are damaged, leading to demyelination and scarring as well as a broad spectrum of signs and symptoms...
.
Function
AntibodyAntibody
An antibody, also known as an immunoglobulin, is a large Y-shaped protein used by the immune system to identify and neutralize foreign objects such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, termed an antigen...
targeting of TIRC7 reveals significant prevention of inflammation
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
in variety of animal model
Animal model
An animal model is a living, non-human animal used during the research and investigation of human disease, for the purpose of better understanding the disease without the added risk of causing harm to an actual human being during the process...
s e.g. rejection
Rejection
The word "rejection" was first used in 1415. The original meaning was "to throw" or "to throw back".Rejection may mean:* Social rejection, in psychology, an interpersonal situation that occurs when a person or group of people exclude an individual from a social relationship* Transplant rejection,...
of transplanted kidney and heart allografts as well as progression of arthritis and EAE. These therapeutic effects were accompanied with significant decreases of Th1 specific cytokine
Cytokine
Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...
s e.g. IFN-gamma, TNF-alpha, IL-2 expression and transcription, induction of CTLA4 whereas IL-10 remained unchanged. The induction of TIRC7 in IL-10 secreting T regulatory cells and the prevention of colitis in the presence of TIRC7 positive T regulatory cells supports the inhibitory signals induced via TIRC7 pathway during immune activation. Further evidence for the inhibitory role of TIRC7 during the course of immune response is that prevention of colitis
Colitis
In medicine, colitis refers to an inflammation of the colon and is often used to describe an inflammation of the large intestine .Colitides may be acute and self-limited or chronic, i.e...
was achievable by a transfer of TIRC7 positive cells
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
into CD45RO mice prior to induction of colitis. The negative immune regulatory role of TIRC7 is furthermore supported by the fact that TIRC7 knock out mice exhibits an increased T and B cell response in the presence of various stimuli in vitro
In vitro
In vitro refers to studies in experimental biology that are conducted using components of an organism that have been isolated from their usual biological context in order to permit a more detailed or more convenient analysis than can be done with whole organisms. Colloquially, these experiments...
and in vivo
In vivo
In vivo is experimentation using a whole, living organism as opposed to a partial or dead organism, or an in vitro controlled environment. Animal testing and clinical trials are two forms of in vivo research...
exhibiting. A significant induced memory cell
Memory cell
Memory cell may refer to:* Memory cell, a building block of computer data storage*Memory B cell, an antibody producing cell*Memory T cell, an infection fighting cell...
subset and reduction of CTLA4 expression observed in TIRC7 knock out mice.
Ligand
The recently identified cell surface ligand to TIRC7 is the non-polymorphic alpha 2 domain (HLA-DRα2) of HLA DR protein. Upon lymphocyte activation TIRC7 is upregulated to engage HLA-DRα2 and induce apoptotic signals in human CD4+ and CD8+ T-cells. The down-regulation of the immune response is achieved via activation of the intrinsic apoptotic pathway by caspaseCaspase
Caspases, or cysteine-aspartic proteases or cysteine-dependent aspartate-directed proteases are a family of cysteine proteases that play essential roles in apoptosis , necrosis, and inflammation....
9, inhibition of lymphocyte proliferation, SHP-1 recruitment, decrease in phosphorylation
Phosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
of STAT4
STAT4
STAT4 is a human gene. The protein encoded by this gene is a member of the STAT protein family of transcription factors....
, TCR-ζ chain and ZAP70 as well as inhibition of FasL expression. HLA-DRα2 and TIRC7 co-localize at the APC-T cell interaction site. In vivo, triggering the HLA-DR-TIRC7 pathway in lipopolysaccaride (LPS
LPS
LPS can stand for more than one thing:* Lipopolysaccharide * Liters per second* Low Pressure Sodium vapor lamps* Leases per second, a speed measure for DHCP servers* Leica Photogrammetry Suite, official name was changed to "LPS" in 2008...
) activated lymphocytes using soluble HLA-DRα2 leads to inhibition of proinflammatory as well as inflammatory
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
cytokines and induction of apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
. These results strongly support the regulatory role of TIRC7 signalling pathway in lymphocyte
Lymphocyte
A lymphocyte is a type of white blood cell in the vertebrate immune system.Under the microscope, lymphocytes can be divided into large lymphocytes and small lymphocytes. Large granular lymphocytes include natural killer cells...
s.
Clinical significance
Mutations in this gene are associated with infantile malignant osteopetrosisOsteopetrosis
Osteopetrosis, literally "stone bone", also known as marble bone disease and Albers-Schonberg disease is an extremely rare inherited disorder whereby the bones harden, becoming denser, in contrast to more prevalent conditions like osteoporosis, in which the bones become less dense and more brittle,...
.