Death receptor 3

Death receptor 3 (DR3), also known as tumor necrosis factor receptor superfamily member 25 (TNFRSF25), is a cell surface receptor of the tumor necrosis factor receptor superfamily which mediates apoptotic signalling and differentiation.[5][6][7] Its only known TNFSF ligand is TNF-like protein 1A (TL1A).[8]

TNFRSF25
Identifiers
Aliases	TNFRSF25, APO-3, DDR3, DR3, LARD, TNFRSF12, TR3, TRAMP, WSL-1, WSL-LR, tumor necrosis factor receptor superfamily member 25, TNF receptor superfamily member 25, GEF720, PLEKHG5
External IDs	OMIM: 603366 MGI: 1934667 HomoloGene: 13202 GeneCards: TNFRSF25
Gene location (Human) Chr. Chromosome 1 (human)[1] Band 1p36.31 Start 6,460,786 bp[1] End 6,466,195 bp[1]
Gene location (Mouse) Chr. Chromosome 4 (mouse)[2] Band 4|4 E2 Start 152,115,934 bp[2] End 152,120,119 bp[2]
Gene ontology Molecular function • tumor necrosis factor-activated receptor activity • signaling receptor activity Cellular component • integral component of membrane • extracellular region • cytosol • cell membrane • integral component of plasma membrane • membrane Biological process • regulation of apoptotic process • multicellular organism development • apoptotic signaling pathway • cell surface receptor signaling pathway • response to lipopolysaccharide • inflammatory response • tumor necrosis factor-mediated signaling pathway • regulation of cell proliferation • immune response • signal transduction • apoptotic process Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	8718	85030
Ensembl	ENSG00000215788	ENSMUSG00000024793
UniProt	Q93038	n/a
RefSeq (mRNA)	NM_148974 NM_001039664 NM_003790 NM_148965 NM_148966 NM_148967 NM_148968 NM_148969 NM_148970	NM_001291010 NM_033042
RefSeq (protein)	NP_001034753 NP_003781 NP_683866 NP_683867 NP_683868 NP_683871	n/a
Location (UCSC)	Chr 1: 6.46 – 6.47 Mb	Chr 4: 152.12 – 152.12 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

Function

The protein encoded by this gene is a member of the TNF-receptor superfamily. This receptor is expressed preferentially by activated and antigen-experienced T lymphocytes. TNFRSF25 is also highly expressed by FoxP3 positive regulatory T lymphocytes. TNFRSF25 is activated by a monogamous ligand, known as TL1A (TNFSF15), which is rapidly upregulated in antigen presenting cells and some endothelial cells following Toll-Like Receptor or Fc receptor activation. This receptor has been shown to signal both through the TRADD adaptor molecule to stimulate NF-kappa B activity or through the FADD adaptor molecule to stimulate caspase activation and regulate cell apoptosis.[6]

Multiple alternatively spliced transcript variants of this gene encoding distinct isoforms have been reported, most of which are potentially secreted molecules. The alternative splicing of this gene in B and T cells encounters a programmed change upon T-cell activation, which predominantly produces full-length, membrane bound isoforms, and is thought to be involved in controlling lymphocyte proliferation induced by T-cell activation. Specifically, activation of TNFRSF25 is dependent upon previous engagement of the T cell receptor. Following binding to TL1A, TNFRSF25 signaling increases the sensitivity of T cells to endogenous IL-2 via the IL-2 receptor and enhances T cell proliferation. Because the activation of the receptor is T cell receptor dependent, the activity of TNFRSF25 in vivo is specific to those T cells that are encountering cognate antigen. At rest, and for individuals without underlying autoimmunity, the majority of T cells that regularly encounter cognate antigen are FoxP3+ regulatory T cells. Stimulation of TNFRSF25, in the absence of any other exogenous signals, stimulates profound and highly specific proliferation of FoxP3+ regulatory T cells from their 8-10% of all CD4+ T cells to 35-40% of all CD4+ T cells within 5 days.[9]

Therapeutics

Therapeutic agonists of TNFRSF25 can be used to stimulate Treg expansion, which can reduce inflammation in experimental models of asthma, allogeneic solid organ transplantation and ocular keratitis.[9][10][11] Similarly, because TNFRSF25 activation is antigen dependent, costimulation of TNFRSF25 together with an autoantigen or with a vaccine antigen can lead to exacerbation of immunopathology or enhanced vaccine-stimulated immunity, respectively.[12] TNFRSF25 stimulation is therefore highly specific to T cell mediated immunity, which can be used to enhance or dampen inflammation depending on the temporal context and quality of foreign vs self antigen availability. Stimulation of TNFRSF25 in humans may lead to similar, but more controllable, effects as costimulatory blockade targeting molecules such as CTLA-4 and PD-1.[7]

References

1. GRCh38: Ensembl release 89: ENSG00000215788 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000024793 - 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. Bodmer JL, Burns K, Schneider P, Hofmann K, Steiner V, Thome M, Bornand T, Hahne M, Schröter M, Becker K, Wilson A, French LE, Browning JL, MacDonald HR, Tschopp J (Jan 1997). "TRAMP, a novel apoptosis-mediating receptor with sequence homology to tumor necrosis factor receptor 1 and Fas(Apo-1/CD95)". Immunity. 6 (1): 79–88. doi:10.1016/S1074-7613(00)80244-7. PMID 9052839.
6. Kitson J, Raven T, Jiang YP, Goeddel DV, Giles KM, Pun KT, Grinham CJ, Brown R, Farrow SN (Nov 1996). "A death-domain-containing receptor that mediates apoptosis". Nature. 384 (6607): 372–5. doi:10.1038/384372a0. PMID 8934525.
7. "Entrez Gene: TNFRSF25 tumor necrosis factor receptor superfamily, member 25".
8. Wang EC (Sep 2012). "On death receptor 3 and its ligands…". Immunology. 137 (1): 114–6. doi:10.1111/j.1365-2567.2012.03606.x. PMC 3449252. PMID 22612445.
9. Schreiber TH, Wolf D, Tsai MS, Chirinos J, Deyev VV, Gonzalez L, Malek TR, Levy RB, Podack ER (Oct 2010). "Therapeutic Treg expansion in mice by TNFRSF25 prevents allergic lung inflammation". The Journal of Clinical Investigation. 120 (10): 3629–40. doi:10.1172/JCI42933. PMC 2947231. PMID 20890040.
10. J Reddy PB, Schreiber TH, Rajasagi NK, Suryawanshi A, Mulik S, Veiga-Parga T, Niki T, Hirashima M, Podack ER, Rouse BT (Oct 2012). "TNFRSF25 agonistic antibody and galectin-9 combination therapy controls herpes simplex virus-induced immunoinflammatory lesions". Journal of Virology. 86 (19): 10606–20. doi:10.1128/JVI.01391-12. PMC 3457251. PMID 22811539.
11. Wolf D, Schreiber TH, Tryphonopoulos P, Li S, Tzakis AG, Ruiz P, Podack ER (Sep 2012). "Tregs expanded in vivo by TNFRSF25 agonists promote cardiac allograft survival". Transplantation. 94 (6): 569–74. doi:10.1097/TP.0b013e318264d3ef. PMID 22902792.
12. Schreiber TH, Wolf D, Bodero M, Gonzalez L, Podack ER (Oct 2012). "T cell costimulation by TNFR superfamily (TNFRSF)4 and TNFRSF25 in the context of vaccination". Journal of Immunology. 189 (7): 3311–8. doi:10.4049/jimmunol.1200597. PMC 3449097. PMID 22956587.

Further reading

• Metheny-Barlow LJ, Li LY (2006). "Vascular endothelial growth inhibitor (VEGI), an endogenous negative regulator of angiogenesis". Seminars in Ophthalmology. 21 (1): 49–58. doi:10.1080/08820530500511446. PMID 16517446.
• Chinnaiyan AM, O'Rourke K, Yu GL, Lyons RH, Garg M, Duan DR, Xing L, Gentz R, Ni J, Dixit VM (Nov 1996). "Signal transduction by DR3, a death domain-containing receptor related to TNFR-1 and CD95". Science. 274 (5289): 990–2. doi:10.1126/science.274.5289.990. PMID 8875942.
• Bonaldo MF, Lennon G, Soares MB (Sep 1996). "Normalization and subtraction: two approaches to facilitate gene discovery". Genome Research. 6 (9): 791–806. doi:10.1101/gr.6.9.791. PMID 8889548.
• Marsters SA, Sheridan JP, Donahue CJ, Pitti RM, Gray CL, Goddard AD, Bauer KD, Ashkenazi A (Dec 1996). "Apo-3, a new member of the tumor necrosis factor receptor family, contains a death domain and activates apoptosis and NF-kappa B". Current Biology. 6 (12): 1669–76. doi:10.1016/S0960-9822(02)70791-4. PMID 8994832.
• Screaton GR, Xu XN, Olsen AL, Cowper AE, Tan R, McMichael AJ, Bell JI (Apr 1997). "LARD: a new lymphoid-specific death domain containing receptor regulated by alternative pre-mRNA splicing". Proceedings of the National Academy of Sciences of the United States of America. 94 (9): 4615–9. doi:10.1073/pnas.94.9.4615. PMC 20772. PMID 9114039.
• Warzocha K, Ribeiro P, Charlot C, Renard N, Coiffier B, Salles G (Jan 1998). "A new death receptor 3 isoform: expression in human lymphoid cell lines and non-Hodgkin's lymphomas". Biochemical and Biophysical Research Communications. 242 (2): 376–9. doi:10.1006/bbrc.1997.7948. PMID 9446802.
• Grenet J, Valentine V, Kitson J, Li H, Farrow SN, Kidd VJ (May 1998). "Duplication of the DR3 gene on human chromosome 1p36 and its deletion in human neuroblastoma". Genomics. 49 (3): 385–93. doi:10.1006/geno.1998.5300. PMID 9615223.
• Jiang Y, Woronicz JD, Liu W, Goeddel DV (Jan 1999). "Prevention of constitutive TNF receptor 1 signaling by silencer of death domains". Science. 283 (5401): 543–6. doi:10.1126/science.283.5401.543. PMID 9915703.
• Kaptein A, Jansen M, Dilaver G, Kitson J, Dash L, Wang E, Owen MJ, Bodmer JL, Tschopp J, Farrow SN (Nov 2000). "Studies on the interaction between TWEAK and the death receptor WSL-1/TRAMP (DR3)". FEBS Letters. 485 (2–3): 135–41. doi:10.1016/S0014-5793(00)02219-5. PMID 11094155.
• Frankel SK, Van Linden AA, Riches DW (Oct 2001). "Heterogeneity in the phosphorylation of human death receptors by p42(mapk/erk2)". Biochemical and Biophysical Research Communications. 288 (2): 313–20. doi:10.1006/bbrc.2001.5761. PMID 11606045.
• Migone TS, Zhang J, Luo X, Zhuang L, Chen C, Hu B, Hong JS, Perry JW, Chen SF, Zhou JX, Cho YH, Ullrich S, Kanakaraj P, Carrell J, Boyd E, Olsen HS, Hu G, Pukac L, Liu D, Ni J, Kim S, Gentz R, Feng P, Moore PA, Ruben SM, Wei P (Mar 2002). "TL1A is a TNF-like ligand for DR3 and TR6/DcR3 and functions as a T cell costimulator". Immunity. 16 (3): 479–92. doi:10.1016/S1074-7613(02)00283-2. PMID 11911831.
• Al-Lamki RS, Wang J, Thiru S, Pritchard NR, Bradley JA, Pober JS, Bradley JR (Aug 2003). "Expression of silencer of death domains and death-receptor-3 in normal human kidney and in rejecting renal transplants". The American Journal of Pathology. 163 (2): 401–11. doi:10.1016/S0002-9440(10)63670-X. PMC 1868232. PMID 12875962.
• Wen L, Zhuang L, Luo X, Wei P (Oct 2003). "TL1A-induced NF-kappaB activation and c-IAP2 production prevent DR3-mediated apoptosis in TF-1 cells". The Journal of Biological Chemistry. 278 (40): 39251–8. doi:10.1074/jbc.M305833200. PMID 12882979.
• Hillman RT, Green RE, Brenner SE (2005). "An unappreciated role for RNA surveillance". Genome Biology. 5 (2): R8. doi:10.1186/gb-2004-5-2-r8. PMC 395752. PMID 14759258.
• Osawa K, Takami N, Shiozawa K, Hashiramoto A, Shiozawa S (Sep 2004). "Death receptor 3 (DR3) gene duplication in a chromosome region 1p36.3: gene duplication is more prevalent in rheumatoid arthritis". Genes and Immunity. 5 (6): 439–43. doi:10.1038/sj.gene.6364097. PMID 15241467.

This article incorporates text from the United States National Library of Medicine, which is in the public domain.