LIGHT (protein) explained

LIGHT, also known as tumor necrosis factor superfamily member 14 (TNFSF14), is a secreted protein of the TNF superfamily.^{[1] [2] [3]} It is recognized by herpesvirus entry mediator (HVEM), as well as decoy receptor 3.

Nomenclature

LIGHT stands for "homologous to lymphotoxin, exhibits inducible expression and competes with HSV glycoprotein D for binding to herpesvirus entry mediator, a receptor expressed on T lymphocytes". In the cluster of differentiation terminology it is classified as CD258.

Function

The protein encoded by this gene is a member of the tumor necrosis factor (TNF) ligand family. This protein is a ligand for TNFRSF14, which is a member of the tumor necrosis factor receptor superfamily, and which is also known as a herpesvirus entry mediator (HVEM). Two alternatively spliced transcript variant encoding distinct isoforms have been reported.^[2]

This protein may function as a costimulatory factor for the activation of lymphoid cells and as a deterrent to infection by herpesvirus. This protein has been shown to stimulate the proliferation of T cells,^[4] trigger apoptosis of various tumor cells^[5] and play a role in vascular normalisation processes.^[6] This protein is also reported to prevent tumor necrosis factor alpha-mediated apoptosis in primary hepatocytes.^[7]

Interactions

LIGHT has been shown to interact with TNFRSF14,^{[8] [9]} TNFRSF6B,^{[8] [9] [10]} BIRC2,^[11] TRAF2^[11] and TRAF3.^[11]

Role in herpes simplex virus

Similar to how CD4 is the primary mediating receptor in HIV infection, the HSV glycoprotein (gD) binds to the HVEM receptor which is demanded by TNFSF14/LIGHT lowering the ability for LIGHT to activate the NFκB pathway. NFκB is a survival factor helping to inhibit apoptosis which triggers a pathway inhibiting caspase 8. When gD from HSV binds to HVEM, LIGHT is non-competitively inhibited from binding, encouraging apoptosis in the infected cell.^[3]

Further reading

• Yang D, Zhai Y, Zhang M . LIGHT, a new member of the TNF superfamily . Journal of Biological Regulators and Homeostatic Agents . 16 . 3 . 206–10 . 2003 . 12456019 .
• Bénichou S, Benmerah A . [The HIV nef and the Kaposi-sarcoma-associated virus K3/K5 proteins: "parasites"of the endocytosis pathway] . Médecine/Sciences . 19 . 1 . 100–6 . January 2003 . 12836198 . 10.1051/medsci/2003191100 . free .
• Anderson JL, Hope TJ . HIV accessory proteins and surviving the host cell . Current HIV/AIDS Reports . 1 . 1 . 47–53 . April 2004 . 16091223 . 10.1007/s11904-004-0007-x . 34731265 .
• Marsters SA, Sheridan JP, Pitti RM, Brush J, Goddard A, Ashkenazi A . Identification of a ligand for the death-domain-containing receptor Apo3 . Current Biology . 8 . 9 . 525–8 . April 1998 . 9560343 . 10.1016/S0960-9822(98)70204-0 . 14953579 . free . 1998CBio....8..525M .
• Zhai Y, Guo R, Hsu TL, Yu GL, Ni J, Kwon BS, Jiang GW, Lu J, Tan J, Ugustus M, Carter K, Rojas L, Zhu F, Lincoln C, Endress G, Xing L, Wang S, Oh KO, Gentz R, Ruben S, Lippman ME, Hsieh SL, Yang D . LIGHT, a novel ligand for lymphotoxin beta receptor and TR2/HVEM induces apoptosis and suppresses in vivo tumor formation via gene transfer . The Journal of Clinical Investigation . 102 . 6 . 1142–51 . September 1998 . 9739048 . 509097 . 10.1172/JCI3492 .
• Harrop JA, McDonnell PC, Brigham-Burke M, Lyn SD, Minton J, Tan KB, Dede K, Spampanato J, Silverman C, Hensley P, DiPrinzio R, Emery JG, Deen K, Eichman C, Chabot-Fletcher M, Truneh A, Young PR . Herpesvirus entry mediator ligand (HVEM-L), a novel ligand for HVEM/TR2, stimulates proliferation of T cells and inhibits HT29 cell growth . The Journal of Biological Chemistry . 273 . 42 . 27548–56 . October 1998 . 9765287 . 10.1074/jbc.273.42.27548 . free .
• Yu KY, Kwon B, Ni J, Zhai Y, Ebner R, Kwon BS . A newly identified member of tumor necrosis factor receptor superfamily (TR6) suppresses LIGHT-mediated apoptosis . The Journal of Biological Chemistry . 274 . 20 . 13733–6 . May 1999 . 10318773 . 10.1074/jbc.274.20.13733 . free .
• Rooney IA, Butrovich KD, Glass AA, Borboroglu S, Benedict CA, Whitbeck JC, Cohen GH, Eisenberg RJ, Ware CF . The lymphotoxin-beta receptor is necessary and sufficient for LIGHT-mediated apoptosis of tumor cells . The Journal of Biological Chemistry . 275 . 19 . 14307–15 . May 2000 . 10799510 . 10.1074/jbc.275.19.14307 . free .
• Lama J, Ware CF . Human immunodeficiency virus type 1 Nef mediates sustained membrane expression of tumor necrosis factor and the related cytokine LIGHT on activated T cells . Journal of Virology . 74 . 20 . 9396–402 . October 2000 . 11000208 . 112368 . 10.1128/JVI.74.20.9396-9402.2000 .
• Morel Y, Schiano de Colella JM, Harrop J, Deen KC, Holmes SD, Wattam TA, Khandekar SS, Truneh A, Sweet RW, Gastaut JA, Olive D, Costello RT . Reciprocal expression of the TNF family receptor herpes virus entry mediator and its ligand LIGHT on activated T cells: LIGHT down-regulates its own receptor . Journal of Immunology . 165 . 8 . 4397–404 . October 2000 . 11035077 . 10.4049/jimmunol.165.8.4397 . free .
• Zhang J, Salcedo TW, Wan X, Ullrich S, Hu B, Gregorio T, Feng P, Qi S, Chen H, Cho YH, Li Y, Moore PA, Wu J . Modulation of T-cell responses to alloantigens by TR6/DcR3 . The Journal of Clinical Investigation . 107 . 11 . 1459–68 . June 2001 . 11390428 . 209323 . 10.1172/JCI12159 .
• Granger SW, Butrovich KD, Houshmand P, Edwards WR, Ware CF . Genomic characterization of LIGHT reveals linkage to an immune response locus on chromosome 19p13.3 and distinct isoforms generated by alternate splicing or proteolysis . Journal of Immunology . 167 . 9 . 5122–8 . November 2001 . 11673523 . 10.4049/jimmunol.167.9.5122 . free .
• Mitchell Kronenberg . Shaikh RB, Santee S, Granger SW, Butrovich K, Cheung T, Kronenberg M, Cheroutre H, Ware CF . Constitutive expression of LIGHT on T cells leads to lymphocyte activation, inflammation, and tissue destruction . Journal of Immunology . 167 . 11 . 6330–7 . December 2001 . 11714797 . 10.4049/jimmunol.167.11.6330 . free .
• Bobik A, Kalinina N . Tumor necrosis factor receptor and ligand superfamily family members TNFRSF14 and LIGHT: new players in human atherogenesis . Arteriosclerosis, Thrombosis, and Vascular Biology . 21 . 12 . 1873–5 . December 2001 . 11742858 . 10.1161/atvb.21.12.1873. free .
• Wang J, Lo JC, Foster A, Yu P, Chen HM, Wang Y, Tamada K, Chen L, Fu YX . The regulation of T cell homeostasis and autoimmunity by T cell-derived LIGHT . The Journal of Clinical Investigation . 108 . 12 . 1771–80 . December 2001 . 11748260 . 209470 . 10.1172/JCI13827 .
• Hsu TL, Chang YC, Chen SJ, Liu YJ, Chiu AW, Chio CC, Chen L, Hsieh SL . Modulation of dendritic cell differentiation and maturation by decoy receptor 3 . Journal of Immunology . 168 . 10 . 4846–53 . May 2002 . 11994433 . 10.4049/jimmunol.168.10.4846 . free .
• Castellano R, Van Lint C, Peri V, Veithen E, Morel Y, Costello R, Olive D, Collette Y . Mechanisms regulating expression of the tumor necrosis factor-related light gene. Role of calcium-signaling pathway in the transcriptional control . The Journal of Biological Chemistry . 277 . 45 . 42841–51 . November 2002 . 12215452 . 10.1074/jbc.M207689200 . free .
• Matsui H, Hikichi Y, Tsuji I, Yamada T, Shintani Y . LIGHT, a member of the tumor necrosis factor ligand superfamily, prevents tumor necrosis factor-alpha-mediated human primary hepatocyte apoptosis, but not Fas-mediated apoptosis . The Journal of Biological Chemistry . 277 . 51 . 50054–61 . December 2002 . 12393901 . 10.1074/jbc.M206562200 . free .

Notes and References

1. Mauri DN, Ebner R, Montgomery RI, Kochel KD, Cheung TC, Yu GL, Ruben S, Murphy M, Eisenberg RJ, Cohen GH, Spear PG, Ware CF . LIGHT, a new member of the TNF superfamily, and lymphotoxin alpha are ligands for herpesvirus entry mediator . Immunity . 8 . 1 . 21–30 . January 1998 . 9462508 . 10.1016/S1074-7613(00)80455-0 . free .
2. Web site: Entrez Gene: TNFSF14 tumor necrosis factor (ligand) superfamily, member 14.
3. Book: Ware . Carl . William . Paul . Fundamental Immunology . limited . Book . 6th . 2008 . Lippincott Williams & Wilkins . Philadelphia . 978-0-7817-6519-0 . 776–801 . Chapter 25: TNF-Related Cytokines in Immunity.
4. Tamada . K . Shimozaki . K . Chapoval . AI . Zhai . Y . Su . J . Chen . SF . Hsieh . SL . Nagata . S . Ni . J . Chen . L . LIGHT, a TNF-like molecule, costimulates T cell proliferation and is required for dendritic cell-mediated allogeneic T cell response. . Journal of Immunology . 15 April 2000 . 164 . 8 . 4105–10 . 10.4049/jimmunol.164.8.4105 . 10754304. 32066617 . free .
5. Rooney . IA . Butrovich . KD . Glass . AA . Borboroglu . S . Benedict . CA . Whitbeck . JC . Cohen . GH . Eisenberg . RJ . Ware . CF . The lymphotoxin-beta receptor is necessary and sufficient for LIGHT-mediated apoptosis of tumor cells. . The Journal of Biological Chemistry . 12 May 2000 . 275 . 19 . 14307–15 . 10.1074/jbc.275.19.14307 . 10799510. free .
6. He . B . Jabouille . A . Steri . V . Johansson-Percival . A . Michael . IP . Kotamraju . VR . Junckerstorff . R . Nowak . AK . Hamzah . J . Lee . G . Bergers . G . Ganss . R . Vascular targeting of LIGHT normalizes blood vessels in primary brain cancer and induces intratumoural high endothelial venules. . The Journal of Pathology . June 2018 . 245 . 2 . 209–221 . 10.1002/path.5080 . 29603739. 6737176 .
7. Matsui . H . Hikichi . Y . Tsuji . I . Yamada . T . Shintani . Y . LIGHT, a member of the tumor necrosis factor ligand superfamily, prevents tumor necrosis factor-alpha-mediated human primary hepatocyte apoptosis, but not Fas-mediated apoptosis. . The Journal of Biological Chemistry . 20 December 2002 . 277 . 51 . 50054–61 . 10.1074/jbc.M206562200 . 12393901. free .
8. Zhang J, Salcedo TW, Wan X, Ullrich S, Hu B, Gregorio T, Feng P, Qi S, Chen H, Cho YH, Li Y, Moore PA, Wu J . Modulation of T-cell responses to alloantigens by TR6/DcR3 . The Journal of Clinical Investigation . 107 . 11 . 1459–68 . June 2001 . 11390428 . 209323 . 10.1172/JCI12159 .
9. Yu KY, Kwon B, Ni J, Zhai Y, Ebner R, Kwon BS . A newly identified member of tumor necrosis factor receptor superfamily (TR6) suppresses LIGHT-mediated apoptosis . The Journal of Biological Chemistry . 274 . 20 . 13733–6 . May 1999 . 10318773 . 10.1074/jbc.274.20.13733 . free .
10. Hsu TL, Chang YC, Chen SJ, Liu YJ, Chiu AW, Chio CC, Chen L, Hsieh SL . Modulation of dendritic cell differentiation and maturation by decoy receptor 3 . Journal of Immunology . 168 . 10 . 4846–53 . May 2002 . 11994433 . 10.4049/jimmunol.168.10.4846 . free .
11. Kuai J, Nickbarg E, Wooters J, Qiu Y, Wang J, Lin LL . Endogenous association of TRAF2, TRAF3, cIAP1, and Smac with lymphotoxin beta receptor reveals a novel mechanism of apoptosis . The Journal of Biological Chemistry . 278 . 16 . 14363–9 . April 2003 . 12571250 . 10.1074/jbc.M208672200 . free .