The TCIRG1 (T cell immune regulator 1) gene encodes for the V-type proton ATPase (V-ATPase) 116 kDa subunit a isoform 3 enzyme.
The TCIRG1 (T cell immune regulator 1) gene encodes for the V-type proton ATPase (V-ATPase) 116 kDa subunit a isoform 3 enzyme.
TCIRG1 (T cell immune regulator 1) is a gene that encodes the V-type proton ATPase (V-ATPase) 116 kDa subunit a isoform 3 enzyme. [5] [6] [7]
Through alternate splicing, the TCIRG1 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.
TIRC7 is a 75 kDa membrane protein, first described in 1998, that plays a central role in T cell activation. [6]
TIRC7 is induced after immune activation [6] on the cell surface of certain peripheral human T and B cells as well as monocytes and IL-10 expressing regulatory T cells. During immune activation, TIRC7 is co-localized with the T cell receptor and CTLA4 within the immune synapse of human T cells. [8] [9] At the protein and mRNA level, its expression is induced in lymphocytes in synovial tissues obtained from patients with rheumatoid arthritis [10] [11] or during rejection of solid organ transplants [12] [13] [14] and bone marrow transplantation [15] as well as in brain tissues obtained from patients with multiple sclerosis. [16] [17] [18]
Antibody targeting of TIRC7 suppresses T cell activation and IL-2 secretion. [6] Specifically, significant prevention of inflammation in a variety of animal models has been shown. These include rejection of transplanted kidney and heart allografts [19] [20] as well as progression of arthritis and experimental autoimmune encephalomyelitis (EAE). These effects were accompanied with significant decreases of Th1 specific cytokines 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 [21] supports the inhibitory signals induced via TIRC7 pathway during immune activation. [22] 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. [23]
The cell surface ligand to TIRC7 is the non-polymorphic alpha 2 domain (HLA-DRα2) of HLA DR protein. [24] 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 caspase 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 lymphocytes.
TCIRG1 mutations affect the a3 subunit of the vacuolar proton pump, which in turn affects the acidification of the bone-osteoclast interface, resulting in infantile malignant osteopetrosis. [25] [26] [7]
CTLA4 or CTLA-4, also known as CD152, is a protein receptor that functions as an immune checkpoint and downregulates immune responses. CTLA4 is constitutively expressed in regulatory T cells but only upregulated in conventional T cells after activation – a phenomenon which is particularly notable in cancers. It acts as an "off" switch when bound to CD80 or CD86 on the surface of antigen-presenting cells.
Vacuolar-type ATPase (V-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. V-ATPases couple the energy of ATP hydrolysis to proton transport across intracellular and plasma membranes of eukaryotic cells. It is generally seen as the polar opposite of ATP synthase because ATP synthase is a proton channel that uses the energy from a proton gradient to produce ATP. V-ATPase however, is a proton pump that uses the energy from ATP hydrolysis to produce a proton gradient.
AP-2 complex subunit mu is a protein that in humans is encoded by the AP2M1 gene.
V-type proton ATPase subunit B, kidney isoform is an enzyme that in humans is encoded by the ATP6V1B1 gene.
V-type proton ATPase subunit E 1 is an enzyme that in humans is encoded by the ATP6V1E1 gene.
V-type proton ATPase subunit B, brain isoform is an enzyme that in humans is encoded by the ATP6V1B2 gene.
V-type proton ATPase 116 kDa subunit a isoform 4 is an enzyme that in humans is encoded by the ATP6V0A4 gene.
V-type proton ATPase subunit C 1 is an enzyme that in humans is encoded by the ATP6V1C1 gene.
V-type proton ATPase 116 kDa subunit a isoform 1 is an enzyme that in humans is encoded by the ATP6V0A1 gene.
V-type proton ATPase catalytic subunit A is an enzyme that in humans is encoded by the ATP6V1A gene.
V-type proton ATPase subunit d 1 is an enzyme that in humans is encoded by the ATP6V0D1 gene.
V-type proton ATPase subunit G 2 is an enzyme that in humans is encoded by the ATP6V1G2 gene.
V-type proton ATPase subunit H is an enzyme that in humans is encoded by the ATP6V1H gene.
V-type proton ATPase subunit G 1 is an enzyme that in humans is encoded by the ATP6V1G1 gene.
V-type proton ATPase subunit D is an enzyme that in humans is encoded by the ATP6V1D gene.
V-type proton ATPase subunit F is an enzyme that in humans is encoded by the ATP6V1F gene.
V-type proton ATPase subunit G 3 is an enzyme that in humans is encoded by the ATP6V1G3 gene.
V-type proton ATPase 21 kDa proteolipid subunit is an enzyme that in humans is encoded by the ATP6V0B gene.
V-type proton ATPase subunit e 1 is an enzyme that in humans is encoded by the ATP6V0E1 gene.
V-type proton ATPase 116 kDa subunit a isoform 2 also known as V-ATPase 116 kDa isoform a2 is an enzyme that in humans is encoded by the ATP6V0A2 gene.
