TCIRG1

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 is a 75 kDa membrane protein, first described in 1998, that plays a central role in T cell activation.{{sfn|Utku et al| 1988}}

TIRC7 is induced after immune activation{{sfn|Utku et al| 1988}} 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.{{cite journal | vauthors = 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 | display-authors = 6 | title = TIRC7 inhibits T cell proliferation by modulation of CTLA-4 expression | journal = Journal of Immunology | volume = 177 | issue = 10 | pages = 6833–41 | date = November 2006 | pmid = 17082597 | doi = 10.4049/jimmunol.177.10.6833 | doi-access = free }}{{cite journal | vauthors = Valk E, Rudd CE, Schneider H | title = CTLA-4 trafficking and surface expression | journal = Trends in Immunology | volume = 29 | issue = 6 | pages = 272–9 | date = June 2008 | pmid = 18468488 | pmc = 4186961 | doi = 10.1016/j.it.2008.02.011 }} At the protein and mRNA level, its expression is induced in lymphocytes in synovial tissues obtained from patients with rheumatoid arthritis{{cite journal | vauthors = Utku N, Heinemann T, Winter M, Bulwin CG, Schlawinsky M, Fraser P, Nieuwenhuis EE, Volk HD, Blumberg RS | display-authors = 6 | title = Antibody targeting of TIRC7 results in significant therapeutic effects on collagen-induced arthritis in mice | journal = Clinical and Experimental Immunology | volume = 144 | issue = 1 | pages = 142–51 | date = April 2006 | pmid = 16542376 | pmc = 1809623 | doi = 10.1111/j.1365-2249.2006.03044.x }}{{cite journal | vauthors = Edwards CJ, Feldman JL, Beech J, Shields KM, Stover JA, Trepicchio WL, Larsen G, Foxwell BM, Brennan FM, Feldmann M, Pittman DD | display-authors = 6 | title = Molecular profile of peripheral blood mononuclear cells from patients with rheumatoid arthritis | journal = Molecular Medicine | volume = 13 | issue = 1–2 | pages = 40–58 | year = 2007 | pmid = 17515956 | pmc = 1869619 | doi = 10.2119/2006-000056.Edwards }} or during rejection of solid organ transplants{{cite journal | vauthors = Tamura A, Milford EL, Utku N | title = TIRC7 pathway as a target for preventing allograft rejection | journal = Drug News & Perspectives | volume = 18 | issue = 2 | pages = 103–8 | date = March 2005 | pmid = 15883619 | doi = 10.1358/dnp.2005.18.2.877163 }}{{cite journal | vauthors = Morgun A, Shulzhenko N, Diniz RV, Almeida DR, Carvalho AC, Gerbase-DeLima M | title = Cytokine and TIRC7 mRNA expression during acute rejection in cardiac allograft recipients | journal = Transplantation Proceedings | volume = 33 | issue = 1–2 | pages = 1610–1 | year = 2001 | pmid = 11267440 | doi = 10.1016/S0041-1345(00)02613-0 }}{{cite journal | vauthors = Shulzhenko N, Morgun A, Rampim GF, Franco M, Almeida DR, Diniz RV, Carvalho AC, Gerbase-DeLima M | display-authors = 6 | title = Monitoring of intragraft and peripheral blood TIRC7 expression as a diagnostic tool for acute cardiac rejection in humans | journal = Human Immunology | volume = 62 | issue = 4 | pages = 342–7 | date = April 2001 | pmid = 11295466 | doi = 10.1016/S0198-8859(01)00211-7 }} and bone marrow transplantation{{cite journal | vauthors = 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 | display-authors = 6 | title = Prediction of graft-versus-host disease in humans by donor gene-expression profiling | journal = PLOS Medicine | volume = 4 | issue = 1 | pages = e23 | date = January 2007 | pmid = 17378698 | pmc = 1796639 | doi = 10.1371/journal.pmed.0040023 | doi-access = free }} {{open access}} as well as in brain tissues obtained from patients with multiple sclerosis.{{sfn|Frischer et al|2014}}{{cite journal | vauthors= Kopitzki K, Hart IK, Loehler J, Boerner A, Blumberg RS, DuPlessis D, Warneke P, Utku N |title= Improvement of acute and established EAE with TIRC7 mAb|journal= J. Neuroimmunol. |volume= 154|pages= 88|year= 2004}}{{cite journal | vauthors = Sellebjerg F, Datta P, Larsen J, Rieneck K, Alsing I, Oturai A, Svejgaard A, Soelberg Sørensen P, Ryder LP | display-authors = 6 | title = Gene expression analysis of interferon-beta treatment in multiple sclerosis | journal = Multiple Sclerosis | volume = 14 | issue = 5 | pages = 615–21 | date = June 2008 | pmid = 18408020 | doi = 10.1177/1352458507085976 | s2cid = 206696484 }}

Antibody targeting of TIRC7 suppresses T cell activation and IL-2 secretion.{{sfn|Utku et al| 1988}} Specifically, significant prevention of inflammation in a variety of animal models has been shown. These include rejection of transplanted kidney and heart allografts{{cite journal | vauthors = Kumamoto Y, Tamura A, Volk HD, Reinke P, Löhler J, Tullius SG, Utku N | title = TIRC7 is induced in rejected human kidneys and anti-TIRC7 mAb with FK506 prolongs survival of kidney allografts in rats | journal = Transplant Immunology | volume = 16 | issue = 3–4 | pages = 238–44 | date = November 2006 | pmid = 17138060 | doi = 10.1016/j.trim.2006.09.027 }}{{cite journal | vauthors = Kumamoto Y, Tomschegg A, Bennai-Sanfourche F, Boerner A, Kaser A, Schmidt-Knosalla I, Heinemann T, Schlawinsky M, Blumberg RS, Volk HD, Utku N | display-authors = 6 | title = Monoclonal antibody specific for TIRC7 induces donor-specific anergy and prevents rejection of cardiac allografts in mice | journal = American Journal of Transplantation | volume = 4 | issue = 4 | pages = 505–14 | date = April 2004 | pmid = 15023142 | doi = 10.1111/j.1600-6143.2004.00367.x | s2cid = 36001054 | doi-access = free }} 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{{cite journal | vauthors = Wakkach A, Augier S, Breittmayer JP, Blin-Wakkach C, Carle GF | title = Characterization of IL-10-secreting T cells derived from regulatory CD4+CD25+ cells by the TIRC7 surface marker | journal = Journal of Immunology | volume = 180 | issue = 9 | pages = 6054–63 | date = May 2008 | pmid = 18424726 | doi = 10.4049/jimmunol.180.9.6054 | doi-access = free }} supports the inhibitory signals induced via TIRC7 pathway during immune activation.{{cite journal | vauthors = Utku N, Heinemann T, Milford EL | title = T-cell immune response cDNA 7 in allograft rejection and inflammation | journal = Current Opinion in Investigational Drugs | volume = 8 | issue = 5 | pages = 401–10 | date = May 2007 | pmid = 17520869 }} 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.{{cite journal | vauthors = Utku N, Boerner A, Tomschegg A, Bennai-Sanfourche F, Bulwin GC, Heinemann T, Loehler J, Blumberg RS, Volk HD | display-authors = 6 | title = TIRC7 deficiency causes in vitro and in vivo augmentation of T and B cell activation and cytokine response | journal = Journal of Immunology | volume = 173 | issue = 4 | pages = 2342–52 | date = August 2004 | pmid = 15294947 | doi = 10.4049/jimmunol.173.4.2342 | doi-access = free }}

The cell surface ligand to TIRC7 is the non-polymorphic alpha 2 domain (HLA-DRα2) of HLA DR protein.{{cite journal | vauthors = 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 | display-authors = 6 | title = 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 | journal = PLOS ONE | volume = 3 | issue = 2 | pages = e1576 | date = February 2008 | pmid = 18270567 | pmc = 2217592 | doi = 10.1371/journal.pone.0001576 | bibcode = 2008PLoSO...3.1576B | editor1-last = Unutmaz | editor1-first = Derya | doi-access = free }} {{open access}} 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.

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.{{cite journal | vauthors = Penna S, Capo V, Palagano E, Sobacchi C, Villa A | title = One Disease, Many Genes: Implications for the Treatment of Osteopetroses | journal = Frontiers in Endocrinology | volume = 10 | pages = 85 | date = 19 February 2019 | pmid = 30837952 | doi = 10.3389/fendo.2019.00085 | pmc = 6389615 | doi-access = free }}{{cite journal | vauthors = Susani L, Pangrazio A, Sobacchi C, Taranta A, Mortier G, Savarirayan R, Villa A, Orchard P, Vezzoni P, Albertini A, Frattini A, Pagani F | display-authors = 6 | title = TCIRG1-dependent recessive osteopetrosis: mutation analysis, functional identification of the splicing defects, and in vitro rescue by U1 snRNA | journal = Human Mutation | volume = 24 | issue = 3 | pages = 225–35 | date = September 2004 | pmid = 15300850 | doi = 10.1002/humu.20076 | s2cid = 31788054 | doi-access = free }}{{sfn|NCBI|2021}}

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

{{reflist|30em}}

{{refbegin | 30em}}

;Journal articles

• {{cite journal | vauthors = Finbow ME, Harrison MA | title = The vacuolar H+-ATPase: a universal proton pump of eukaryotes | journal = The Biochemical Journal | volume = 324 ( Pt 3) | issue = Pt 3 | pages = 697–712 | date = June 1997 | pmid = 9210392 | pmc = 1218484 | doi = 10.1042/bj3240697 }}
• {{cite journal | vauthors = Forgac M | title = Structure and properties of the vacuolar (H+)-ATPases | journal = The Journal of Biological Chemistry | volume = 274 | issue = 19 | pages = 12951–4 | date = May 1999 | pmid = 10224039 | doi = 10.1074/jbc.274.19.12951 | doi-access = free }}
• {{cite journal | vauthors = Frattini A, Orchard PJ, Sobacchi C, Giliani S, Abinun M, Mattsson JP, Keeling DJ, Andersson AK, Wallbrandt P, Zecca L, Notarangelo LD, Vezzoni P, Villa A | display-authors = 6 | title = Defects in TCIRG1 subunit of the vacuolar proton pump are responsible for a subset of human autosomal recessive osteopetrosis | journal = Nature Genetics | volume = 25 | issue = 3 | pages = 343–6 | date = July 2000 | pmid = 10888887 | doi = 10.1038/77131 | s2cid = 21316081 }}
• {{cite journal |last1=Frischer |first1=Jm |last2=Reindl |first2=M |last3=Künz |first3=B |last4=Berger |first4=T |last5=Schmidt |first5=S |last6=Milford |first6=El |last7=Knosp |first7=E |last8=Lassmann |first8=H |last9=Utku |first9=N |title=TIRC7 and HLA-DR axis contributes to inflammation in multiple sclerosis |journal=Multiple Sclerosis Journal |date=August 2014 |volume=20 |issue=9 |pages=1171–1181 |doi=10.1177/1352458514521516 |pmid=24526664|s2cid=38090185 |ref={{harvid|Frischer et al|2014}}}}
• {{cite journal |last1=Heinemann |first1=T |last2=Bulwin |first2=GC |last3=Randall |first3=J |last4=Schnieders |first4=B |last5=Sandhoff |first5=K |last6=Volk |first6=HD |last7=Milford |first7=E |last8=Gullans |first8=SR |last9=Utku |first9=N |title=Genomic organization of the gene coding for TIRC7, a novel membrane protein essential for T cell activation. |journal=Genomics |date=1 May 1999 |volume=57 |issue=3 |pages=398–406 |doi=10.1006/geno.1999.5751 |pmid=10329006}}
• {{cite journal | vauthors = Kane PM | title = Introduction: V-ATPases 1992-1998 | journal = Journal of Bioenergetics and Biomembranes | volume = 31 | issue = 1 | pages = 3–5 | date = February 1999 | pmid = 10340843 | doi = 10.1023/A:1001884227654 }}
• {{cite journal | vauthors = Kawasaki-Nishi S, Nishi T, Forgac M | title = Proton translocation driven by ATP hydrolysis in V-ATPases | journal = FEBS Letters | volume = 545 | issue = 1 | pages = 76–85 | date = June 2003 | pmid = 12788495 | doi = 10.1016/S0014-5793(03)00396-X | bibcode = 2003FEBSL.545...76K | s2cid = 10507213 }}
• {{cite journal | vauthors = Kornak U, Schulz A, Friedrich W, Uhlhaas S, Kremens B, Voit T, Hasan C, Bode U, Jentsch TJ, Kubisch C | display-authors = 6 | title = Mutations in the a3 subunit of the vacuolar H(+)-ATPase cause infantile malignant osteopetrosis | journal = Human Molecular Genetics | volume = 9 | issue = 13 | pages = 2059–63 | date = August 2000 | pmid = 10942435 | doi = 10.1093/hmg/9.13.2059 | doi-access = free }}
• {{cite journal | vauthors = Morel N | title = Neurotransmitter release: the dark side of the vacuolar-H+ATPase | journal = Biology of the Cell | volume = 95 | issue = 7 | pages = 453–7 | date = October 2003 | pmid = 14597263 | doi = 10.1016/S0248-4900(03)00075-3 | s2cid = 17519696 | doi-access = free }}
• {{cite journal | vauthors = Nelson N, Harvey WR | title = Vacuolar and plasma membrane proton-adenosinetriphosphatases | journal = Physiological Reviews | volume = 79 | issue = 2 | pages = 361–85 | date = April 1999 | pmid = 10221984 | doi = 10.1152/physrev.1999.79.2.361 | s2cid = 1477911 }}
• {{cite journal | vauthors = Nishi T, Forgac M | title = The vacuolar (H+)-ATPases--nature's most versatile proton pumps | journal = Nature Reviews. Molecular Cell Biology | volume = 3 | issue = 2 | pages = 94–103 | date = February 2002 | pmid = 11836511 | doi = 10.1038/nrm729 | s2cid = 21122465 | doi-access = free }}
• {{cite journal | vauthors = Stevens TH, Forgac M | title = Structure, function and regulation of the vacuolar (H+)-ATPase | journal = Annual Review of Cell and Developmental Biology | volume = 13 | pages = 779–808 | year = 1998 | pmid = 9442887 | doi = 10.1146/annurev.cellbio.13.1.779 }}
• {{cite journal | vauthors = Utku N, Heinemann T, Tullius SG, Bulwin GC, Beinke S, Blumberg RS, Beato F, Randall J, Kojima R, Busconi L, Robertson ES, Schülein R, Volk HD, Milford EL, Gullans SR | display-authors = 6 | title = Prevention of acute allograft rejection by antibody targeting of TIRC7, a novel T cell membrane protein | journal = Immunity | volume = 9 | issue = 4 | pages = 509–18 | date = October 1998 | pmid = 9806637 | doi = 10.1016/S1074-7613(00)80634-2|ref={{harvid|Utku et al| 1988}} | doi-access = free }}
• {{cite journal | vauthors = Wieczorek H, Brown D, Grinstein S, Ehrenfeld J, Harvey WR | title = Animal plasma membrane energization by proton-motive V-ATPases | journal = BioEssays | volume = 21 | issue = 8 | pages = 637–48 | date = August 1999 | pmid = 10440860 | doi = 10.1002/(SICI)1521-1878(199908)21:8<637::AID-BIES3>3.0.CO;2-W | s2cid = 23505139 }}

;Websites

• {{cite web |title=TCIRG1 gene |url=https://medlineplus.gov/genetics/gene/tcirg1/ |website=MedlinePlus |access-date=21 March 2021 |language=en |date=18 August 2020|publisher=National Library of Medicine|ref={{harvid|Medline|2020}}}}
• {{cite web |title=TCIRG1 |url=https://www.wikigenes.org/e/gene/e/10312.html |website=Wikigenes |date=13 October 2011|ref={{harvid|Wikigenes|2011}}}}
• {{cite web |title=TCIRG1: T cell immune regulator 1, ATPase H+ transporting V0 subunit a3 [Homo sapiens (human)] |url=https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=10312 |website=Gene |publisher=NCBI |access-date=22 March 2021 |date=16 March 2021|ref={{harvid|NCBI|2021}}}}
• {{cite web | title = TCIRG7 (search)| url = https://www.ncbi.nlm.nih.gov/sites/entrez?db=nuccore&cmd=search&term=TIRC7|website=Nucleotide |publisher=NCBI |access-date=24 March 2021 |ref={{harvid|NCBI|2021a}}}}

{{refend}}

• {{UCSC genome browser|TCIRG1}}
• {{UCSC gene details|TCIRG1}}

{{ATPase}}