TCIRG1

V-type proton ATPase 116 kDa subunit a isoform 3 is an enzyme that in humans is encoded by the TCIRG1 gene.[5][6][7]

TCIRG1
Identifiers
Aliases	TCIRG1, ATP6N1C, ATP6V0A3, Atp6i, OC-116kDa, OC116, OPTB1, Stv1, TIRC7, Vph1, a3, T-cell immune regulator 1, ATPase H+ transporting V0 subunit a3, T cell immune regulator 1, ATPase H+ transporting V0 subunit a3
External IDs	OMIM: 604592 MGI: 1350931 HomoloGene: 4392 GeneCards: TCIRG1
Gene location (Human) Chr. Chromosome 11 (human)[1] Band 11q13.2 Start 68,039,016 bp[1] End 68,050,895 bp[1]
Gene location (Mouse) Chr. Chromosome 19 (mouse)[2] Band 19 A|19 3.62 cM Start 3,896,050 bp[2] End 3,907,133 bp[2]
RNA expression pattern More reference expression data
Gene ontology Molecular function • transporter activity • ATPase binding • proton-transporting ATPase activity, rotational mechanism • hydrogen ion transmembrane transporter activity Cellular component • integral component of membrane • proton-transporting V-type ATPase, V0 domain • phagocytic vesicle membrane • membrane • vacuolar proton-transporting V-type ATPase, V0 domain • cell membrane • integral component of plasma membrane • lysosomal membrane • apical plasma membrane • mitochondrion • vacuolar proton-transporting V-type ATPase complex • endosome membrane • ficolin-1-rich granule membrane • cell nucleus • lysosome • late endosome • secretory granule membrane • phagocytic vesicle Biological process • protein catabolic process in the vacuole • insulin receptor signaling pathway • transferrin transport • vacuolar proton-transporting V-type ATPase complex assembly • ion transport • vacuolar acidification • cellular defense response • ion transmembrane transport • positive regulation of cell proliferation • ATP synthesis coupled proton transport • macroautophagy • phagosome acidification • neutrophil degranulation • transport • hydrogen ion transmembrane transport • ossification • osteoclast proliferation • immunoglobulin production • cellular calcium ion homeostasis • apoptotic process • inflammatory response • regulation of proton transport • response to silver ion • regulation of gene expression • immunoglobulin mediated immune response • optic nerve development • myeloid cell differentiation • B cell differentiation • T cell differentiation • osteoclast differentiation • memory T cell activation • T-helper 1 cell activation • odontogenesis • T cell homeostasis • tooth eruption • bone resorption • regulation of osteoblast differentiation • pH reduction • homeostasis of number of cells • regulation of insulin secretion • retina development in camera-type eye • hematopoietic stem cell homeostasis • enamel mineralization • cellular response to cytokine stimulus • interferon-gamma secretion • dentin mineralization Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	10312	27060
Ensembl	ENSG00000110719	ENSMUSG00000001750
UniProt	Q13488	n/a
RefSeq (mRNA)	NM_006019 NM_006053 NM_001351059	NM_001136091 NM_001167784 NM_016921
RefSeq (protein)	NP_006010 NP_006044 NP_001337988	n/a
Location (UCSC)	Chr 11: 68.04 – 68.05 Mb	Chr 19: 3.9 – 3.91 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

Function

Through alternate splicing, 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:

• 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 start site that is within exon 5 of variant 1 followed by an intron as part of its 5' UTR.[8]

TIRC7

Expression

TIRC7 is a membrane protein 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[9][10] At the protein and mRNA level, its expression is induced in lymphocytes in synovial tissues obtained from patients with rheumatoid arthritis[11][12] or during rejection of solid organ transplants[13][14][15] and bone marrow transplantation[16] as well as in brain tissues obtained from patients with multiple sclerosis.[17][18]

Function

Antibody targeting of TIRC7 reveals significant prevention of inflammation in variety of animal models e.g. rejection of transplanted kidney and heart allografts[19][20] as well as progression of arthritis and EAE. These therapeutic 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]

Ligand

The recently identified 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.

Clinical significance

Mutations in this gene are associated with infantile malignant osteopetrosis.[7]

See also

• T cell
• Co-stimulation
• MHC class II
• CTLA-4
• apoptosis

References

1. GRCh38: Ensembl release 89: ENSG00000110719 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000001750 - 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. Li YP, Chen W, Stashenko P (Mar 1996). "Molecular cloning and characterization of a putative novel human osteoclast-specific 116-kDa vacuolar proton pump subunit". Biochem Biophys Res Commun. 218 (3): 813–21. doi:10.1006/bbrc.1996.0145. PMID 8579597.
6. Utku N, Heinemann T, Tullius SG, Bulwin GC, Beinke S, Blumberg RS, Beato F, Randall J, Kojima R, Busconi L, Robertson ES, Schulein R, Volk HD, Milford EL, Gullans SR (Nov 1998). "Prevention of acute allograft rejection by antibody targeting of TIRC7, a novel T cell membrane protein". Immunity. 9 (4): 509–18. doi:10.1016/S1074-7613(00)80634-2. PMID 9806637.
7. "Entrez Gene: TCIRG1 T-cell, immune regulator 1, ATPase, H+ transporting, lysosomal V0 subunit A3".
8. "NCBI Nucleotide: Homo sapiens T-cell, immune regulator 1, ATPase, H+ transporting, lysosomal V0 subunit A3 (TCIRG1)".
9. Bulwin GC, Heinemann T, Bugge V, Winter M, Lohan A, Schlawinsky M, Schulze A, Wälter S, Sabat R, Schülein R, Wiesner B, Veh RW, Löhler J, Blumberg RS, Volk HD, Utku N (November 2006). "TIRC7 inhibits T cell proliferation by modulation of CTLA-4 expression". Journal of Immunology. 177 (10): 6833–41. doi:10.4049/jimmunol.177.10.6833. PMID 17082597.
10. Valk E, Rudd CE, Schneider H (June 2008). "CTLA-4 trafficking and surface expression". Trends Immunol. 29 (6): 272–9. doi:10.1016/j.it.2008.02.011. PMC 4186961. PMID 18468488.
11. Utku N, Heinemann T, Winter M, Bulwin CG, Schlawinsky M, Fraser P, Nieuwenhuis EE, Volk HD, Blumberg RS (April 2006). "Antibody targeting of TIRC7 results in significant therapeutic effects on collagen-induced arthritis in mice". Clin. Exp. Immunol. 144 (1): 142–51. doi:10.1111/j.1365-2249.2006.03044.x. PMC 1809623. PMID 16542376.
12. Edwards CJ, Feldman JL, Beech J, Shields KM, Stover JA, Trepicchio WL, Larsen G, Foxwell BM, Brennan FM, Feldmann M, Pittman DD (2007). "Molecular Profile of Peripheral Blood Mononuclear Cells from Patients with Rheumatoid Arthritis". Mol. Med. 13 (1–2): 40–58. doi:10.2119/2006-000056.Edwards. PMC 1869619. PMID 17515956.
13. Tamura A, Milford EL, Utku N (March 2005). "TIRC7 pathway as a target for preventing allograft rejection". Drug News Perspect. 18 (2): 103–8. doi:10.1358/dnp.2005.18.2.877163. PMID 15883619.
14. Morgun A, Shulzhenko N, Diniz RV, Almeida DR, Carvalho AC, Gerbase-DeLima M (2001). "Cytokine and TIRC7 mRNA expression during acute rejection in cardiac allograft recipients". Transplant. Proc. 33 (1–2): 1610–1. doi:10.1016/S0041-1345(00)02613-0. PMID 11267440.
15. Shulzhenko N, Morgun A, Rampim GF, Franco M, Almeida DR, Diniz RV, Carvalho AC, Gerbase-DeLima M (April 2001). "Monitoring of intragraft and peripheral blood TIRC7 expression as a diagnostic tool for acute cardiac rejection in humans". Hum. Immunol. 62 (4): 342–7. doi:10.1016/S0198-8859(01)00211-7. PMID 11295466.
16. Baron C, Somogyi R, Greller LD, Rineau V, Wilkinson P, Cho CR, Cameron MJ, Kelvin DJ, Chagnon P, Roy DC, Busque L, Sékaly RP, Perreault C (January 2007). "Prediction of Graft-Versus-Host Disease in Humans by Donor Gene-Expression Profiling". PLoS Med. 4 (1): e23. doi:10.1371/journal.pmed.0040023. PMC 1796639. PMID 17378698.
17. Kopitzki K, Hart IK, Loehler J, Boerner A, Blumberg RS, DuPlessis D, Warneke P, Utku N (2004). "Improvement of acute and established EAE with TIRC7 mAb". J. Neuroimmunol. 154: 88.
18. Sellebjerg F, Datta P, Larsen J, Rieneck K, Alsing I, Oturai A, Svejgaard A, Soelberg Sørensen P, Ryder LP (June 2008). "Gene expression analysis of interferon-beta treatment in multiple sclerosis". Mult. Scler. 14 (5): 615–21. doi:10.1177/1352458507085976. PMID 18408020.
19. Kumamoto Y, Tamura A, Volk HD, Reinke P, Löhler J, Tullius SG, Utku N (November 2006). "TIRC7 is induced in rejected human kidneys and anti-TIRC7 mAb with FK506 prolongs survival of kidney allografts in rats". Transpl. Immunol. 16 (3–4): 238–44. doi:10.1016/j.trim.2006.09.027. PMID 17138060.
20. Kumamoto Y, Tomschegg A, Bennai-Sanfourche F, Boerner A, Kaser A, Schmidt-Knosalla I, Heinemann T, Schlawinsky M, Blumberg RS, Volk HD, Utku N (April 2004). "Monoclonal antibody specific for TIRC7 induces donor-specific anergy and prevents rejection of cardiac allografts in mice". Am. J. Transplant. 4 (4): 505–14. doi:10.1111/j.1600-6143.2004.00367.x. PMID 15023142.
21. Wakkach A, Augier S, Breittmayer JP, Blin-Wakkach C, Carle GF (May 2008). "Characterization of IL-10-secreting T cells derived from regulatory CD4+CD25+ cells by the TIRC7 surface marker". Journal of Immunology. 180 (9): 6054–63. doi:10.4049/jimmunol.180.9.6054. PMID 18424726.
22. Utku N, Heinemann T, Milford EL (May 2007). "T-cell immune response cDNA 7 in allograft rejection and inflammation". Current Opinion in Investigational Drugs. 8 (5): 401–10. PMID 17520869.
23. Utku N, Boerner A, Tomschegg A, Bennai-Sanfourche F, Bulwin GC, Heinemann T, Loehler J, Blumberg RS, Volk HD (August 2004). "TIRC7 deficiency causes in vitro and in vivo augmentation of T and B cell activation and cytokine response". Journal of Immunology. 173 (4): 2342–52. doi:10.4049/jimmunol.173.4.2342. PMID 15294947.
24. Bulwin GC, Wälter S, Schlawinsky M, Heinemann T, Schulze A, Höhne W, Krause G, Kalka-Moll W, Fraser P, Volk HD, Löhler J, Milford EL, Utku N (2008). Unutmaz D (ed.). "HLA-DR Alpha 2 Mediates Negative Signalling via Binding to Tirc7 Leading to Anti-Inflammatory and Apoptotic Effects in Lymphocytes In Vitro and In Vivo". PLoS ONE. 3 (2): e1576. doi:10.1371/journal.pone.0001576. PMC 2217592. PMID 18270567.

Further reading

• Finbow ME, Harrison MA (1997). "The vacuolar H+-ATPase: a universal proton pump of eukaryotes". Biochem. J. 324 (Pt 3): 697–712. doi:10.1042/bj3240697. PMC 1218484. PMID 9210392.
• Stevens TH, Forgac M (1998). "Structure, function and regulation of the vacuolar (H+)-ATPase". Annu. Rev. Cell Dev. Biol. 13: 779–808. doi:10.1146/annurev.cellbio.13.1.779. PMID 9442887.
• Nelson N, Harvey WR (1999). "Vacuolar and plasma membrane proton-adenosinetriphosphatases". Physiol. Rev. 79 (2): 361–85. doi:10.1152/physrev.1999.79.2.361. PMID 10221984.
• Forgac M (1999). "Structure and properties of the vacuolar (H+)-ATPases". J. Biol. Chem. 274 (19): 12951–4. doi:10.1074/jbc.274.19.12951. PMID 10224039.
• Kane PM (1999). "Introduction: V-ATPases 1992-1998". J. Bioenerg. Biomembr. 31 (1): 3–5. doi:10.1023/A:1001884227654. PMID 10340843.
• Wieczorek H, Brown D, Grinstein S, et al. (1999). "Animal plasma membrane energization by proton-motive V-ATPases". BioEssays. 21 (8): 637–48. doi:10.1002/(SICI)1521-1878(199908)21:8<637::AID-BIES3>3.0.CO;2-W. PMID 10440860.
• Nishi T, Forgac M (2002). "The vacuolar (H+)-ATPases--nature's most versatile proton pumps". Nature Reviews Molecular Cell Biology. 3 (2): 94–103. doi:10.1038/nrm729. PMID 11836511.
• Kawasaki-Nishi S, Nishi T, Forgac M (2003). "Proton translocation driven by ATP hydrolysis in V-ATPases". FEBS Lett. 545 (1): 76–85. doi:10.1016/S0014-5793(03)00396-X. PMID 12788495.
• Morel N (2004). "Neurotransmitter release: the dark side of the vacuolar-H+ATPase". Biol. Cell. 95 (7): 453–7. doi:10.1016/S0248-4900(03)00075-3. PMID 14597263.
• Heinemann T, Bulwin GC, Randall J, et al. (1999). "Genomic organization of the gene coding for TIRC7, a novel membrane protein essential for T cell activation". Genomics. 57 (3): 398–406. doi:10.1006/geno.1999.5751. PMID 10329006.
• Frattini A, Orchard PJ, Sobacchi C, et al. (2000). "Defects in TCIRG1 subunit of the vacuolar proton pump are responsible for a subset of human autosomal recessive osteopetrosis". Nat. Genet. 25 (3): 343–6. doi:10.1038/77131. PMID 10888887.
• Kornak U, Schulz A, Friedrich W, et al. (2000). "Mutations in the a3 subunit of the vacuolar H(+)-ATPase cause infantile malignant osteopetrosis". Hum. Mol. Genet. 9 (13): 2059–63. doi:10.1093/hmg/9.13.2059. PMID 10942435.

External links

• TCIRG1 human gene location in the UCSC Genome Browser.
• TCIRG1 human gene details in the UCSC Genome Browser.