TCIRG1

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; OMA:TCIRG1 - orthologs
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 3,946,050 bp[2] End 3,957,133 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in granulocyte blood spleen body of pancreas right adrenal cortex left adrenal cortex canal of the cervix gastric mucosa upper lobe of left lung right lung Top expressed in stroma of bone marrow granulocyte body of femur thymus decidua internal carotid artery tibiofemoral joint mesenteric lymph nodes external carotid artery duodenum More reference expression data BioGPS More reference expression data
Gene ontology Molecular function transporter activity ATPase binding proton-transporting ATPase activity, rotational mechanism proton 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 plasma 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 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 population proliferation ATP synthesis coupled proton transport macroautophagy phagosome acidification neutrophil degranulation transport proton 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 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: 3.95 – 3.96 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

The TCIRG1 (T cell immune regulator 1) gene encodes for the V-type proton ATPase (V-ATPase) 116 kDa subunit a isoform 3 enzyme.

Gene

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]

Function

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:

• 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.

TIRC7

TIRC7 is a 75 kDa membrane protein, first described in 1998, that plays a central role in T cell activation.[6]

Expression

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]

Function

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]

Ligand

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.

Clinical significance

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]

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 (January 1996). "Molecular cloning and characterization of a putative novel human osteoclast-specific 116-kDa vacuolar proton pump subunit". Biochemical and Biophysical Research Communications. 218 (3): 813–21. doi:10.1006/bbrc.1996.0145. PMID 8579597.
6. Utku et al 1988.
7. NCBI 2021.
8. Bulwin GC, Heinemann T, Bugge V, Winter M, Lohan A, Schlawinsky M, et al. (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.
9. Valk E, Rudd CE, Schneider H (June 2008). "CTLA-4 trafficking and surface expression". Trends in Immunology. 29 (6): 272–9. doi:10.1016/j.it.2008.02.011. PMC 4186961. PMID 18468488.
10. Utku N, Heinemann T, Winter M, Bulwin CG, Schlawinsky M, Fraser P, et al. (April 2006). "Antibody targeting of TIRC7 results in significant therapeutic effects on collagen-induced arthritis in mice". Clinical and Experimental Immunology. 144 (1): 142–51. doi:10.1111/j.1365-2249.2006.03044.x. PMC 1809623. PMID 16542376.
11. Edwards CJ, Feldman JL, Beech J, Shields KM, Stover JA, Trepicchio WL, et al. (2007). "Molecular profile of peripheral blood mononuclear cells from patients with rheumatoid arthritis". Molecular Medicine. 13 (1–2): 40–58. doi:10.2119/2006-000056.Edwards. PMC 1869619. PMID 17515956.
12. Tamura A, Milford EL, Utku N (March 2005). "TIRC7 pathway as a target for preventing allograft rejection". Drug News & Perspectives. 18 (2): 103–8. doi:10.1358/dnp.2005.18.2.877163. PMID 15883619.
13. 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". Transplantation Proceedings. 33 (1–2): 1610–1. doi:10.1016/S0041-1345(00)02613-0. PMID 11267440.
14. Shulzhenko N, Morgun A, Rampim GF, Franco M, Almeida DR, Diniz RV, et al. (April 2001). "Monitoring of intragraft and peripheral blood TIRC7 expression as a diagnostic tool for acute cardiac rejection in humans". Human Immunology. 62 (4): 342–7. doi:10.1016/S0198-8859(01)00211-7. PMID 11295466.
15. Baron C, Somogyi R, Greller LD, Rineau V, Wilkinson P, Cho CR, et al. (January 2007). "Prediction of graft-versus-host disease in humans by donor gene-expression profiling". PLOS Medicine. 4 (1): e23. doi:10.1371/journal.pmed.0040023. PMC 1796639. PMID 17378698.
16. Frischer et al 2014.
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, et al. (June 2008). "Gene expression analysis of interferon-beta treatment in multiple sclerosis". Multiple Sclerosis. 14 (5): 615–21. doi:10.1177/1352458507085976. PMID 18408020. S2CID 206696484.
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". Transplant Immunology. 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, et al. (April 2004). "Monoclonal antibody specific for TIRC7 induces donor-specific anergy and prevents rejection of cardiac allografts in mice". American Journal of Transplantation. 4 (4): 505–14. doi:10.1111/j.1600-6143.2004.00367.x. PMID 15023142. S2CID 36001054.
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, et al. (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, et al. (February 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. Bibcode:2008PLoSO...3.1576B. doi:10.1371/journal.pone.0001576. PMC 2217592. PMID 18270567.
25. Penna S, Capo V, Palagano E, Sobacchi C, Villa A (19 February 2019). "One Disease, Many Genes: Implications for the Treatment of Osteopetroses". Frontiers in Endocrinology. 10: 85. doi:10.3389/fendo.2019.00085. PMC 6389615. PMID 30837952.
26. Susani L, Pangrazio A, Sobacchi C, Taranta A, Mortier G, Savarirayan R, et al. (September 2004). "TCIRG1-dependent recessive osteopetrosis: mutation analysis, functional identification of the splicing defects, and in vitro rescue by U1 snRNA". Human Mutation. 24 (3): 225–35. doi:10.1002/humu.20076. PMID 15300850. S2CID 31788054.

Bibliography

Journal articles

• Finbow ME, Harrison MA (June 1997). "The vacuolar H+-ATPase: a universal proton pump of eukaryotes". The Biochemical Journal. 324 ( Pt 3) (Pt 3): 697–712. doi:10.1042/bj3240697. PMC 1218484. PMID 9210392.
• Forgac M (May 1999). "Structure and properties of the vacuolar (H+)-ATPases". The Journal of Biological Chemistry. 274 (19): 12951–4. doi:10.1074/jbc.274.19.12951. PMID 10224039.
• Frattini A, Orchard PJ, Sobacchi C, Giliani S, Abinun M, Mattsson JP, et al. (July 2000). "Defects in TCIRG1 subunit of the vacuolar proton pump are responsible for a subset of human autosomal recessive osteopetrosis". Nature Genetics. 25 (3): 343–6. doi:10.1038/77131. PMID 10888887. S2CID 21316081.
• Frischer, Jm; Reindl, M; Künz, B; Berger, T; Schmidt, S; Milford, El; Knosp, E; Lassmann, H; Utku, N (August 2014). "TIRC7 and HLA-DR axis contributes to inflammation in multiple sclerosis". Multiple Sclerosis Journal. 20 (9): 1171–1181. doi:10.1177/1352458514521516. PMID 24526664. S2CID 38090185.
• Heinemann, T; Bulwin, GC; Randall, J; Schnieders, B; Sandhoff, K; Volk, HD; Milford, E; Gullans, SR; Utku, N (1 May 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.
• Kane PM (February 1999). "Introduction: V-ATPases 1992-1998". Journal of Bioenergetics and Biomembranes. 31 (1): 3–5. doi:10.1023/A:1001884227654. PMID 10340843.
• Kawasaki-Nishi S, Nishi T, Forgac M (June 2003). "Proton translocation driven by ATP hydrolysis in V-ATPases". FEBS Letters. 545 (1): 76–85. Bibcode:2003FEBSL.545...76K. doi:10.1016/S0014-5793(03)00396-X. PMID 12788495. S2CID 10507213.
• Kornak U, Schulz A, Friedrich W, Uhlhaas S, Kremens B, Voit T, et al. (August 2000). "Mutations in the a3 subunit of the vacuolar H(+)-ATPase cause infantile malignant osteopetrosis". Human Molecular Genetics. 9 (13): 2059–63. doi:10.1093/hmg/9.13.2059. PMID 10942435.
• Morel N (October 2003). "Neurotransmitter release: the dark side of the vacuolar-H+ATPase". Biology of the Cell. 95 (7): 453–7. doi:10.1016/S0248-4900(03)00075-3. PMID 14597263. S2CID 17519696.
• Nelson N, Harvey WR (April 1999). "Vacuolar and plasma membrane proton-adenosinetriphosphatases". Physiological Reviews. 79 (2): 361–85. doi:10.1152/physrev.1999.79.2.361. PMID 10221984. S2CID 1477911.
• Nishi T, Forgac M (February 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. S2CID 21122465.
• Stevens TH, Forgac M (1998). "Structure, function and regulation of the vacuolar (H+)-ATPase". Annual Review of Cell and Developmental Biology. 13: 779–808. doi:10.1146/annurev.cellbio.13.1.779. PMID 9442887.
• Utku N, Heinemann T, Tullius SG, Bulwin GC, Beinke S, Blumberg RS, et al. (October 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.
• Wieczorek H, Brown D, Grinstein S, Ehrenfeld J, Harvey WR (August 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. S2CID 23505139.

Websites

• "TCIRG1 gene". MedlinePlus. National Library of Medicine. 18 August 2020. Retrieved 21 March 2021.
• "TCIRG1". Wikigenes. 13 October 2011.
• "TCIRG1: T cell immune regulator 1, ATPase H+ transporting V0 subunit a3 [Homo sapiens (human)]". Gene. NCBI. 16 March 2021. Retrieved 22 March 2021.
• "TCIRG7 (search)". Nucleotide. NCBI. Retrieved 24 March 2021.

External links

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