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RefSeq (mRNA)



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V-type proton ATPase 116 kDa subunit a isoform 3 is an enzyme that in humans is encoded by the TCIRG1 gene.[1][2][3]


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.[4]



TIRC7 is a membrane protein induced after immune activation[2] 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[5][6] At the protein and mRNA level, its expression is induced in lymphocytes in synovial tissues obtained from patients with rheumatoid arthritis[7][8] or during rejection of solid organ transplants[9][10][11] and bone marrow transplantation[12] as well as in brain tissues obtained from patients with multiple sclerosis.[13][14]


Antibody targeting of TIRC7 reveals significant prevention of inflammation in variety of animal models e.g. rejection of transplanted kidney and heart allografts[15][16] 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[17] supports the inhibitory signals induced via TIRC7 pathway during immune activation.[18] 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.[19]


The recently identified cell surface ligand to TIRC7 is the non-polymorphic alpha 2 domain (HLA-DRα2) of HLA DR protein.[20] 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.[3]

See also


  1. 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.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  2. 2.0 2.1 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.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  3. 3.0 3.1 "Entrez Gene: TCIRG1 T-cell, immune regulator 1, ATPase, H+ transporting, lysosomal V0 subunit A3".<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  4. "NCBI Nucleotide: Homo sapiens T-cell, immune regulator 1, ATPase, H+ transporting, lysosomal V0 subunit A3 (TCIRG1)".<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  5. 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.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  6. Valk E, Rudd CE, Schneider H (June 2008). "CTLA-4 trafficking and surface expression". Trends Immunol. 29 (6): 272–9. doi:10.1016/ PMC 4186961. PMID 18468488.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  7. 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.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  8. 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.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  9. 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.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  10. 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.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  11. 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.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  12. 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.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles> open access publication – free to read
  13. 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.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  14. 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.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  15. 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.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  16. 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.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  17. 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.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  18. 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.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  19. 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.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  20. 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.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles> open access publication – free to read

Further reading

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  • 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.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  • 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.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  • Nelson N, Harvey WR (1999). "Vacuolar and plasma membrane proton-adenosinetriphosphatases". Physiol. Rev. 79 (2): 361–85. PMID 10221984.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  • 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.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  • Kane PM (1999). "Introduction: V-ATPases 1992-1998". J. Bioenerg. Biomembr. 31 (1): 3–5. doi:10.1023/A:1001884227654. PMID 10340843.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  • 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.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  • 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.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  • 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.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  • 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.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  • 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.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  • 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.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  • 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.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>

External links