V-ATPase subunit a

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V-ATPase subunit a
Properties of human protein
Mass / length primary structure 830 amino acids
Secondary to quaternary structure Membrane protein, part of the V-ATPase
Isoforms Long, short
Identifier
Gene names TCIRG1  ; ATP6V0A3
External IDs
Occurrence
Parent taxon Creature

The V-ATPase subunit a is a protein found in the cell and vacuole membranes of many living things. It is a subunit of the V-ATPase complex, more precisely subunit a of the V-ATPase proton channel. As such, it is essential as a proton pump for endocytosis and the normal function of lysosomes . The short isoform of the subunit ( TIRC7 ), on the other hand, functions in the activation of T cells as part of the immune response . Mutations that affect the Long isoform result in the rare hereditary disease autosomal recessive osteopetrosis .

Using alternative splicing, the TCIRG1 gene codes for two proteins with different functions. The long isoform (also OC116) acts as a V-ATPase subunit exclusively in osteoclasts . The short isoform, which lacks the first 216 amino acids, is usually referred to as TIRC7 (from English T-cell immune response cDNA 7 ). It is expressed in lymphoid tissue and on T lymphocytes and is essential for normal T cell activation.

Short isoform (TIRC7)

Gene expression

TIRC7 is a membrane protein which, after activation of the immune system , is induced on the surface of cells and on various peripheral human T cells and B cells as well as on monocytes and interleukin-10 expressing regulatory T cells. TIRC7 is colocalized with the T-cell receptor and with CTLA-4 during the immune response within the immunological synapse . At the protein and mRNA level, TIRC7 expression is upregulated in the following tissues and diseases: Lymphocytes of the synovial fluid of patients with rheumatoid arthritis, during the rejection reaction of organ transplants, after bone marrow transplantation and in brain tissue of patients with multiple sclerosis.

function

By treatment with the anti-TIRC7- antibodies can be used in a variety of animal models, an the one hand, inflammation of rheumatoid arthritis and EAE, the rejection of allogeneic kidney and heart grafts, on the other hand, the progression can be prevented. These therapeutic effects are evident in a reduction in Th1-specific cytokines, e.g. B. interferon (IFN) -gamma, tumor necrosis factor (TNF) -alpha, interleukin-2 (expression and transcription) and induction of CTLA4, while IL-10 expression is not affected. The induction of TIRC7 in IL-10-secreting regulatory T cells and the prevention of colitis in the presence of TIRC7-positive regulatory T cells support the thesis of the induction of inhibitory signals via the TIRC7 signaling pathway during immune activation. Further evidence for the inhibitory role of TIRC7 is that the occurrence of the disease could be prevented by the transfer of TIRC7-positive cells in the CD45RO mouse model before the induction of the colitis. The negative immunoregulatory role of TIRC7 is further supported by the fact that the TIRC7 knockout mouse exhibits an increased T and B cell response in the presence of a large number of different stimuli in vitro and in vivo . A significantly induced memory T cell population and a reduction in CTLA4 expression are also observed in the TIRC7 knockout mouse.

Ligand

The recently identified cell surface ligand of TIRC7 is the non-polymorphic alpha 2 domain (HLA-DRα2) of HLA-DR (see also Human Leukocyte Antigen ). After T-cell activation, TIRC7 is upregulated in order to bind HLA-DRα2 and to induce apoptotic signals in human CD4 + and CD8 + T cells. The downregulation of the immune response is achieved through the activation of the intrinsic signaling pathway of apoptosis by caspase 9, the inhibition of lymphocyte cell division , the binding of SHP-1, the reduction of the phosphorylation of STAT4, TCR-ζ and ZAP70 as well as the inhibition of FasL expression reached. HLA-DRα2 and TIRC7 are co-localized at the contact point between the antigen presenting cell and the T cell. In vivo, the activation of the HLA-DR-TIRC7 signaling pathway in lipopolysaccharide (LPS) activated lymphocytes by soluble HLA-DRα2 leads to an inhibition of proinflammatory and inflammatory cytokines and induction of apoptosis. These results strongly support the regulatory role of the TIRC7 signaling pathway in lymphocytes.

See also

Individual evidence

  1. ↑ IPR002490 ATPase, V0 / A0 complex, 116kDa subunit. In: InterPro. EBI, accessed October 28, 2010 .
  2. ↑ Entrez Genes: TCIRG1 T-cell, immune regulator 1, ATPase, H + transporting, lysosomal V0 subunit A3 . Retrieved March 7, 2011.
  3. ↑ Heinemann T, Bulwin GC, Randall J, et al. : Genomic organization of the gene coding for TIRC7, a novel membrane protein essential for T cell activation. . In: Genomics . 57, No. 3, 1999, pp. 398-406. doi : 10.1006 / geno.1999.5751 . PMID 10329006 .
  4. ↑ UniProt Q13488
  5. ↑ NCBI nucleotides: Homo sapiens T-cell, immune regulator 1, ATPase, H + transporting, lysosomal V0 subunit A3 (TCIRG1) . Retrieved March 7, 2011.
  6. ↑ Utku N, Heinemann T, Tullius SG, et al. : Prevention of acute allograft rejection by antibody targeting of TIRC7, a novel T cell membrane protein. . In: Immunity . 9, No. 4, 1998, pp. 509-518. PMID 9806637 .
  7. ↑ Bulwin GC, Heinemann T, Bugge V, Winter M, Lohan A, Schlawinsky M, Schulze A, Wälters S, Sabat R, Schülein R, Wiesner B, Veh RW, Löhler J, Blumberg RS, Volk HD, Utku N .: TIRC7 inhibits T cell proliferation by modulation of CTLA-4 expression. . In: J Immunol. . 177, No. 10, 2006, pp. 6833-6841. PMID 17082597 .
  8. ↑ Valk E, Rudd CE, Schneider H .: CTLA-4 trafficking and surface expression. . In: Trends Immunol . . 29, No. 6, 2008, pp. 272-279. PMID 18468488 .
  9. ↑ Utku N, Heinemann T, Winter M, Bulwin CG, Schlawinsky M, Fraser P, Nieuwenhuis EE, Volk HD, Blumberg RS .: Antibody targeting of TIRC7 results in significant therapeutic effects on collagen-induced arthritis in mice. . In: Clin Exp Immunol. . 144, No. 1, 2006, pp. 142-151. PMID 16542376 .
  10. ↑ Edwards CJ, Feldman JL, Beech J, Shields KM, Stover JA, Trepicchio WL, Larsen G, Foxwell BM, Brennan FM, Feldmann M, Pittman DD .: Molecular profile of peripheral blood mononuclear cells from patients with rheumatoid arthritis. . In: Mol Med. . 13, No. 1-2, 2007, pp. 40-58. PMID 17515956 .
  11. ↑ Tamura A, Milford EL, Utku N .: TIRC7 pathway as a target for preventing allograft rejection. . In: Drug News Perspect. . 18, No. 2, 2005, pp. 103-108. PMID 15883619 .
  12. ↑ Morgun A, Shulzhenko N, Diniz RV, Almeida DR, Carvalho AC, Gerbase-DeLima M .: Cytokine and TIRC7 mRNA expression during acute rejection in cardiac allograft recipients. . In: Transplant Proc. . 33, No. 1-2, 2001, pp. 1610-1611. PMID 11267440 .
  13. ↑ Shulzhenko N, Morgun A, Rampim GF, Franco M, Almeida DR, Diniz RV, Carvalho AC, Gerbase-DeLima M .: Monitoring of intragraft and peripheral blood TIRC7 expression as a diagnostic tool for acute cardiac rejection in humans. . In: Hum Immunol. . 62, No. 4, 2001, pp. 342-347. PMID 11295466 .
  14. ↑ 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 .: Prediction of graft-versus-host disease in humans by donor gene-expression profiling. . In: PLoS Med . . 4, No. 1, 2007, p. E23. PMID 17378698 .
  15. ↑ Kopitzki, K Hart IK, Loehler J, Boerner A, Blumberg RS, DuPlessis D, Warneke P, Utku N .: Improvement of acute and established EAE with TIRC7 mAb. . In: J Neuroimmunol. . 154, 2004, p. 88.
  16. ↑ Sellebjerg F, Datta P, Larsen J, Rieneck K, Alsing I, Oturai A, Svejgaard A, Soelberg Sørensen P, Ryder L .: Gene expression analysis of interferon {beta} treatment in multiple sclerosis. . In: Mult Scler. . 14, No. 5, 2008, pp. 615-621. PMID 18408020 .
  17. ↑ Kumamoto Y, Tamura A, Volk HD, Reinke P, Löhler J, Tullius SG, Utku N .: TIRC7 is induced in rejected human kidneys and anti-TIRC7 mAb with FK506 prolongs survival of kidney allografts in rats. . In: Transpl Immunol . 16, No. 3-4, 2006, pp. 238-244. PMID 17138060 .
  18. ↑ Kumamoto Y, Tomschegg A, Bennai-Sanfourche F, Boerner A, Kaser A, Schmidt-Knosalla I, Heinemann T, Schlawinsky M, Blumberg RS, Volk HD, Utku N .: Monoclonal antibody specific for TIRC7 induces donor-specific anergy and Rejection of cardiac prevents allografts in mice. . In: Am J Transplant . 4, No. 4, 2004, pp. 505-514. PMID 15023142 .
  19. ↑ Wakkach A, Augier S, Breittmayer JP, Blin-Wakkach C, Carle GF .: Characterization of IL-10-secreting T cells derived from regulatory CD4 + CD25 + cells by the TIRC7 surface marker. . In: J Immunol . 180, No. 9, 2008, pp. 6054-6063. PMID 18424726 .
  20. ↑ Utku N, Heinemann T, Milford EL .: T-cell immune response cDNA 7 in allograft rejection and inflammation. . In: Curr Opin Investig Drugs . 8, No. 5, 2007, pp. 401-410. PMID 17520869 .
  21. ↑ Utku N, Boerner A, Tomschegg A, Bennai-Sanfourche F, Bulwin GC, Heinemann T, Loehler J, Blumberg RS, Volk HD: TIRC7 deficiency causes in vitro and in vivo augmentation of T and B cell activation and cytokine response. . In: J Immunol . 173, No. 4, 2004, pp. 2342-2352. PMID 15294947 .
  22. ↑ Bulwin GC, Wälters S, Schlawinsky M, Heinemann T, Schulze A, Höhne W, Krause G, Kalka-Moll W, Fraser P, Volk HD, Löhler J, Milford EL, Utku N .: HLA-DR alpha 2 mediates negative signaling via binding to Tirc7 leading to anti-inflammatory and apoptotic effects in lymphocytes in vitro and in vivo. . In: PLoS ONE. . 3, No. 2, 2008, p. E1576. PMID 18270567 .