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)
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]
Ligand
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]
↑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. PMID15883619.
↑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. PMID11267440.
↑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. PMID11295466.
↑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.
↑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. PMID18408020.
↑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. PMID17138060.
↑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. PMID15023142.
↑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. PMID18424726.
↑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. PMID17520869.
↑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. PMID15294947.
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. PMID9442887.
Nelson N, Harvey WR (1999). "Vacuolar and plasma membrane proton-adenosinetriphosphatases". Physiol. Rev. 79 (2): 361–85. PMID10221984.
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. PMID11836511.
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. PMID12788495.
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. PMID10329006.
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. PMID10888887.
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. PMID10942435.
