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The LTβR Signaling Pathway

  • Paula S. Norris
  • Carl F. Ware
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 597)

Abstract

The lymphotoxin-β receptor (LTβR, TNFRSF3) signaling pathway activates gene transcription programs and cell death important in immune development and host defense. The TNF receptor associated factors (TRAF)-2, 3 and 5 function as adaptors linking LTβR signaling targets. Interestingly, TRAF deficient mice do not phenocopy mice deficient in components of the LTβR pathway, presenting a conundrum. Here, an update of our understanding and models of the LTβR signaling pathway are reviewed, with a focus on this conundrum.

Keywords

NFKB Activation Peripheral Lymphoid Organ Tumor Necrosis Factor Superfamily Tumor Necrosis Factor Receptor Associate Factor Herpes Virus Entry Mediator 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. 1.
    Locksley RM, Killeen N, Lenardo MJ. The TNF and TNF receptor superfamilies: Integrating mammalian biology. Cell 2001; 104:487–501.PubMedCrossRefGoogle Scholar
  2. 2.
    Schneider K, Potter KG, Ware CF. Lymphotoxin and LIGHT signaling pathways and target genes. Immunol Rev 2004; 202:49–66.PubMedCrossRefGoogle Scholar
  3. 3.
    Ware CF. Network communications: Lymphotoxins, LIGHT, and TNF. Annu Rev Immunol 2005; 23:787–819.PubMedCrossRefGoogle Scholar
  4. 4.
    Baens M, Chaffanet M, Cassiman JJ et al. Construction and evaluation of a hncDNA library of human 12p transcribed sequences derived from a somatic cell hybrid. Genomics 1993; 16:214–218.PubMedCrossRefGoogle Scholar
  5. 5.
    Force WR, Walter BN, Hession C et al. Mouse lymphotoxin-β receptor. Molecular genetics, ligand binding, and expression. J Immunol 1996; 155:5280–5288.Google Scholar
  6. 6.
    Murphy M, Walter BN, Pike-Nobile L et al. Expression of the lymphotoxin β-receptor on follicular stromal cells in human lymphoid tissue. Cell Death Differ 1998; 5:497–505.PubMedCrossRefGoogle Scholar
  7. 7.
    Browning, JL, Sizing ID, Lawton P et al. Characterization of lymphotoxin-alpha beta complexes on the surface of mouse lymphocytes. J Immunol 1997; 159(7):3288–3298.PubMedGoogle Scholar
  8. 8.
    Ehlers S, Holscher C, Scheu S et al. The lymphotoxin beta receptor is critically involved in controlling infections with the intracellular pathogens Mycobacterium tuberculosis and Listeria monocytogenes. J Immunol 2003; 170:5210–5218.PubMedGoogle Scholar
  9. 9.
    Stopfer P, Mannel DN, Hehlgans T. Lymphotoxin-beta receptor activation by activated T cells induces cytokine release from mouse bone marrow-derived mast cells. J Immunol 2004; 172:7459–7465.PubMedGoogle Scholar
  10. 10.
    Browning JL, French LE. Visualization of lymphotoxin-beta and lymphotoxin-beta receptor expression in mouse embryos. J Immunol 2002; 168:5079–5087.PubMedGoogle Scholar
  11. 11.
    Kabashima K, Banks TA, Ansel KM et al. Intrinsic lymphotoxin-beta receptor requirement for homeostasis of lymphoid tissue dendritic cells. Immunity 2005; 22:439–450.PubMedCrossRefGoogle Scholar
  12. 12.
    Crowe PD, VanArsdale TL, Walter BN et al. A lymphotoxin-beta-specific receptor. Science 1994; 264:707–710.PubMedCrossRefGoogle Scholar
  13. 13.
    Mauri DN, Ebner R, Montgomery RI et al. LIGHT, a new member of the TNF superfamily and lymphotoxin α are ligands for herpesvirus entry mediator. Immunity 1998; 8:21–30.PubMedCrossRefGoogle Scholar
  14. 14.
    Sung HH, Juang JH, Lin YC et al. Transgenic expression of decoy receptor 3 protects islets from spontaneous and chemical-induced autoimmune destruction in nonobese diabetic mice. J Exp Med 2004; 199:1143–1151.PubMedCrossRefGoogle Scholar
  15. 15.
    Sedy JR, Gavrieli M, Potter KG et al. B and T lymphocyte attenuator regulates T cell activation through interaction with herpesvirus entry mediator. Nat Immunol 2005; 6:90–98.PubMedCrossRefGoogle Scholar
  16. 16.
    Croft M. The evolving crosstalk between costimulatory and coinhibitory receptors: HVEM-BTLA. Trends Immunol 2005; 26:292–294.PubMedCrossRefGoogle Scholar
  17. 17.
    Cheung TC, Humphreys IR, Potter KG et al. Evolutionarily divergent herpesviruses modulate T cell activation by targeting the herpesvirus entry mediator cosignaling pathway. Proc Natl Acad Sci USA 2005; 102:13218–13223.PubMedCrossRefGoogle Scholar
  18. 18.
    Watts TH, Gommerman JL. The LIGHT and DARC sides of herpesvirus entry mediator. Proc Natl Acad Sci USA 2005; 102:13365–13366.PubMedCrossRefGoogle Scholar
  19. 19.
    Arch R, Gedrich R, Thompson C. Tumor necrosis factor receptor-associated factors (TRAFs)—a family of adapter proteins that regulates life and death. Genes Dev 1998; 12:2821–2830.PubMedGoogle Scholar
  20. 20.
    VanArsdale TL, VanArsdale SL, Force WR et al. Lymphotoxin-β receptor signaling complex: Role of tumor necrosis factor receptor-associated factor 3 recruitment in cell death and activation of nuclear factor kB. Proc Natl Acad Sci 1997; 94:2460–2465.PubMedCrossRefGoogle Scholar
  21. 21.
    Mosialos G, Birkenbach M, Yalamanchili R et al. The Epstein-Barr virus transforming protein LMP1 engages signaling proteins for the tumor necrosis factor receptor family. Cell 1995; 80:389–399.PubMedCrossRefGoogle Scholar
  22. 22.
    Nakano H, Oshima H, Chung W et al. TRAF5, an activator of NF-κB and putative signal transducer for the lymphotoxin-β receptor. J Biol Chem 1996; 271:14661–14664.PubMedCrossRefGoogle Scholar
  23. 23.
    Matsumoto M, Hsieh TY, Zhu N et al. Hepatitis C virus core protein interacts with the cytoplasmic tail of lymphotoxin-β receptor. J Virol 1997; 71:1301–1309.PubMedGoogle Scholar
  24. 24.
    Krajewska M, Krajewski S, Zapata JM et al. TRAF-4 expression in epithelial progenitor cells. Analysis in normal adult, fetal, and tumor tissues. Am J Pathol 1998; 152:1549–1561.PubMedGoogle Scholar
  25. 25.
    Force WR, Glass AA, Benedict CA et al. Discrete signaling regions in the lymphotoxin-β receptor for TRAF binding, subcellular localization and activation of cell death and NFκB pathways. J Biol Chem 2000; 275:11121–11129.PubMedCrossRefGoogle Scholar
  26. 26.
    Ghosh S, May M, Kopp E. NF-κB and REL proteins: Evolutionarily conserved mediators of immune responses. Ann Rev Immunol 1998; 16:225–260.CrossRefGoogle Scholar
  27. 27.
    Karin M, Ben-Neriah Y. Phosphorylation meets ubiquitination: The control of NF-[kappa]B activity. Annu Rev Immunol 2000; 18:621–663.PubMedCrossRefGoogle Scholar
  28. 28.
    Ghosh S, Karin M. Missing pieces in the NF-kappaB puzzle. Cell 2002; 109(Suppl):S81–96.CrossRefGoogle Scholar
  29. 29.
    Pomerantz JL, Baltimore D. Two pathways to NF-kappaB. Mol Cell 2002; 10:693–695.PubMedCrossRefGoogle Scholar
  30. 30.
    Dejardin E, Droin NM, Delhase M et al. The lymphotoxin-beta receptor induces different patterns of gene expression via two NF-kappaB pathways. Immunity 2002; 17:525–535.PubMedCrossRefGoogle Scholar
  31. 31.
    Xiao G, Harhaj EW, Sun SC. NF-kappaB-inducing kinase regulates the processing of NF-kappaB2 p100. Mol Cell 2001; 7:401–409.PubMedCrossRefGoogle Scholar
  32. 32.
    Malinin NL, Boldin MP, Kovalenko AV et al. MAP3K-related kinase involved in NF-kappaB induction by TNF, CD95 and IL-1. Nature 1997; 385:540–544.PubMedCrossRefGoogle Scholar
  33. 33.
    Song HY, Regnier CH, Kirschning CJ et al. Tumor necrosis factor (TNF)-mediated kinase cascades: Bifurcation of nuclear factor-kappaB and c-jun N-terminal kinase (JNK/SAPK) pathways at TNF receptor-associated factor 2. Proc Natl Acad Sci USA 1997; 94(18):9792–9796.PubMedCrossRefGoogle Scholar
  34. 34.
    Kayagaki N, Yan M, Seshasayee D et al. BAFF/BLyS receptor 3 binds the B cell survival factor BAFF ligand through a discrete surface loop and promotes processing of NF-kappaB2. Immunity 2002; 17:515–524.PubMedCrossRefGoogle Scholar
  35. 35.
    Claudio E, Brown K, Park S et al. BAFF-induced NEMO-independent processing of NF-kappa B2 in maturing B cells. Nat Immunol 2002; 3:958–965.PubMedCrossRefGoogle Scholar
  36. 36.
    Coope HJ, Atkinson PG, Huhse B et al. CD40 regulates the processing of NF-kappaB2 p100 to p52. EMBO J 2002; 21:5375–5385.PubMedCrossRefGoogle Scholar
  37. 37.
    Luftig M, Yasui T, Soni V et al. Epstein-Barr virus latent infection membrane protein 1 TRAF-binding site induces NIK/IKKα-dependent noncanonical NFκB activation. Proc Natl Acad Sci USA 2004; 101:141–146.PubMedCrossRefGoogle Scholar
  38. 38.
    Ramakrishnan P, Wang W, Wallach D. Receptor-specific signaling for both the alternative and the canonical NF-kappaB activation pathways by NF-kappaB-inducing kinase. Immunity 2004; 21:477–489.PubMedCrossRefGoogle Scholar
  39. 39.
    Lin X, Mu Y, Cunningham Jr ET et al. Molecular determinants of NF-kappaB-inducing kinase action. Mol Cell Biol 1998; 18:5899–5907.PubMedGoogle Scholar
  40. 40.
    Matsushima A, Kaisho T, Rennert PD et al. Essential role of nuclear factor (NF)-kappaB-inducing kinase and inhibitor of kappaB (IkappaB) kinase alpha in NF-kappaB activation through lymphotoxin beta receptor, but not through tumor necrosis factor receptor I. J Exp Med 2001; 193:631–636.PubMedCrossRefGoogle Scholar
  41. 41.
    Luftig MA, Cahir-McFarland E, Mosialos G et al. Effects of the NIK aly mutation on NF-kappaB activation by the Epstein-Barr virus latent infection membrane protein, lymphotoxin beta receptor and CD40. J Biol Chem 2001; 276:14602–14606.PubMedCrossRefGoogle Scholar
  42. 43.
    Liao G, Sun SC. Negative regulation of the nuclear factor kappa B-inducing kinase by a cis-acting domain. J Biol Chem 2000; 275:21081–21085.CrossRefGoogle Scholar
  43. 43.
    Liao G, Zhang M, Harhaj EW et al. Regulation of the NF-κB inducing kinase by TRAF3-induced degradation. J Biol Chem 2004; 279:26243–26250.PubMedCrossRefGoogle Scholar
  44. 44.
    Xiao G, Fong A, Sun SC. Induction of p100 processing by NF-kappaB-inducing kinase involves docking IKKalpha to p100 and IKKalpha-mediated phosphorylation. J Biol Chem 2004; 279:30099–105.PubMedCrossRefGoogle Scholar
  45. 45.
    Kim YS, Nedospasov SA, Liu ZG. TRAF2 plays a key, nonredundant role in LIGHT-lymphotoxin beta receptor signaling. Mol Cell Biol 2005; 25:2130–2137.PubMedCrossRefGoogle Scholar
  46. 46.
    Whitmarsh ADR. Transcription factor AP-1 regulation by mitogen-activated protein kinase signal transduction pathways. J Mol Med 1996; 74:589–607.PubMedCrossRefGoogle Scholar
  47. 47.
    Cross TG, Scheel-Toellner D, Henriquez NV et al. Serine/threonine protein kinases and apoptosis. Exp Cell Res 2000; 256:34–41.PubMedCrossRefGoogle Scholar
  48. 48.
    Marsters SA, Ayres TM, Skuatch M et al. Herpesvirus entry mediator, a member of the tumor necrosis factor receptor family (TNFR), interacts with members of the TNFR-associated factor family and activates the transcription factors NF-kB and AP-1. J Biol Chem 1997; 272:14029–14032.PubMedCrossRefGoogle Scholar
  49. 49.
    Chang YH, Hsieh SL, Chen MC et al. Lymphotoxin beta receptor induces interleukin 8 gene expression via NF-kappaB and AP-1 activation. Exp Cell Res 2002; 278:166–174.PubMedCrossRefGoogle Scholar
  50. 50.
    Browning JL, Miatkowski K, Sizing I et al. Signalling through the lymphotoxin-β receptor induces the death of some adenocarcinoma tumor lines. J Exp Med 1996; 183:867–878.PubMedCrossRefGoogle Scholar
  51. 51.
    Rooney IA, Buttrovich KD, Glass AA et al. The lymphotoxin-beta receptor is necessary and sufficient for LIGHT-mediated apoptosis of tumor cells. J Biol Chem 2000; 275:14307–14315.PubMedCrossRefGoogle Scholar
  52. 52.
    Wu MY, Wang PY, Han SH et al. The cytoplasmic domain of the lymphotoxin-beta receptor mediates cell death in HeLa cells. J Biol Chem 1999; 274:11868–11873.PubMedCrossRefGoogle Scholar
  53. 53.
    Chen MC, Hsu TL, Luh TY et al. Overexpression of bcl-2 enhances LIGHT-and interferon-gamma-mediated apoptosis in Hep3BT2 cells. J Biol Chem 2000; 275:38794–38801.PubMedCrossRefGoogle Scholar
  54. 54.
    Wilson CA, Browning JL. Death of HT29 adenocarcinoma cells induced by TNF family receptor activation is caspase-independent and displays features of both apoptosis and necrosis. Cell Death Differ 2002; 9:1321–1333.PubMedCrossRefGoogle Scholar
  55. 55.
    Chen MC, Hwang MJ, Chou YC et al. The role of apoptosis signal-regulating kinase 1 in lymphotoxin-beta receptor-mediated cell death. J Biol Chem 2003; 278:16073–16081.PubMedCrossRefGoogle Scholar
  56. 56.
    Rothe M, Pan MG, Henzel WJ et al. The TNFR2-TRAF signaling complex contains two novel proteins related to baculoviral inhibitor of apoptosis proteins. Cell 1995; 83:1243–1252.PubMedCrossRefGoogle Scholar
  57. 57.
    Kuai J, Nickbarg E, Wooters J et al. Endogenous association of TRAF2, TRAF3, cIAP1 and Smac with lymphotoxin beta receptor reveals a novel mechanism of apoptosis. J Biol Chem 2003; 278:14363–14369.PubMedCrossRefGoogle Scholar
  58. 58.
    Li C, Norris PS, Ni CZ et al. Structurally distinct recognition motifs in lymphotoxin-beta receptor and CD40 for tumor necrosis factor receptor-associated factor (TRAF)-mediated signaling. J Biol Chem 2003; 278:50523–50529.PubMedCrossRefGoogle Scholar
  59. 59.
    Ni CZ, Welsh K, Leo E et al. Molecular basis for CD40 signaling mediated by TRAF3. Proc Natl Acad Sci USA 2000; 97:10395–10399.PubMedCrossRefGoogle Scholar
  60. 60.
    Li C, Ni CZ, Havert ML et al. Downstream regulator TANK binds to the CD40 recognition site on TRAF3. Structure (Camb) 2002; 10:403–411.CrossRefGoogle Scholar
  61. 61.
    Ni CZ, Oganesyan G, Welsh K et al. Key molecular contacts promote recognition of the BAFF receptor by TNF receptor-associated factor 3: Implications for intracellular signaling regulation. J Immunol 2004; 173:7394–7400.PubMedGoogle Scholar
  62. 62.
    Najmanovich R, Kuttner J, Sobolev V et al. Side-chain flexibility in proteins upon ligand binding. Proteins 2000; 39:261–268.PubMedCrossRefGoogle Scholar
  63. 63.
    DeLano WL. Unraveling hot spots in binding interfaces: Progress and challenges. Curr Opin Struct Biol 2002; 12:14–20.PubMedCrossRefGoogle Scholar
  64. 64.
    Weih F, Caamano J. Regulation of secondary lymphoid organ development by the nuclear factor-kappaB signal transduction pathway. Immunol Rev 2003; 195:91–105.PubMedCrossRefGoogle Scholar
  65. 65.
    Ansel KM, Ngo VN, Hyman PL et al. A chemokine-driven positive feedback loop organizes lymphoid follicles. Nature 2000; 406:309–314.PubMedCrossRefGoogle Scholar
  66. 66.
    Rumbo M, Sierro F, Debard N et al. Lymphotoxin beta receptor signaling induces the chemokine CCL20 in intestinal epithelium. Gastroenterology 2004; 127:213–223.PubMedCrossRefGoogle Scholar
  67. 67.
    Huber C, Thielen C, Seeger H et al. Lymphotoxin-beta receptor-dependent genes in lymph node and follicular dendritic cell transcriptomes. J Immunol 2005; 174:5526–5536.PubMedGoogle Scholar
  68. 68.
    De Togni P, Goellner J, Ruddle NH et al. Abnormal development of peripheral lymphoid organs in mice deficient in lymphotoxin. Science 1994; 264:703–706.PubMedCrossRefGoogle Scholar
  69. 69.
    Banks TA, Rouse BT, Kerley MK et al. Lymphotoxin-alpha-deficient mice. Effects on secondary lymphoid organ development and humoral immune responsiveness. J Immunol 1995; 155:1685–1693.PubMedGoogle Scholar
  70. 70.
    Nishikawa S, Honda K, Vieira P et al. Organogenesis of peripheral lymphoid organs. Immunol Rev 2003; 195:72–80.PubMedCrossRefGoogle Scholar
  71. 71.
    Georgopoulos K, Bigby M, Wang J et al. The Ikaros gene is required for the development of all lymphoid lineages. Cell 1994; 79:143–156.PubMedCrossRefGoogle Scholar
  72. 72.
    Yokota Y, Mansouri A, Mori S et al. Development of peripheral lymphoid organs and natural killer cells depends on the helix-loop-helix inhibitor Id2. Nature 1999; 397:702–706.PubMedCrossRefGoogle Scholar
  73. 73.
    Sun Z, Unutmaz D, Zou YR et al. Requirement for RORgamma in thymocyte survival and lymphoid organ development. Science 2000; 288:2369–2373.PubMedCrossRefGoogle Scholar
  74. 74.
    Kurebayashi S, Ueda E, Sakaue M et al. Retinoid-related orphan receptor gamma (RORgamma) is essential for lymphoid organogenesis and controls apoptosis during thymopoiesis. Proc Natl Acad Sci USA 2000; 97:10132–10137.PubMedCrossRefGoogle Scholar
  75. 75.
    Eberl G, Marmon S, Sunshine MJ et al. An essential function for the nuclear receptor RORgamma(t) in the generation of fetal lymphoid tissue inducer cells. Nat Immunol 2004; 5:64–73.PubMedCrossRefGoogle Scholar
  76. 76.
    Fu YX, Chaplin D. Development and maturation of secondary lymphoid tissues. Annu Rev Immunol 1999; 17:399–433.PubMedCrossRefGoogle Scholar
  77. 77.
    Yeh WC, Shahinian A, Speiser D et al. Early lethality, functional NF-kappaB activation and increased sensitivity to TNF-induced cell death in TRAF2-deficient mice. Immunity 1997; 7:715–725.PubMedCrossRefGoogle Scholar
  78. 78.
    Yeh WC, Hakem R, Woo M et al. Gene targeting in the analysis of mammalian apoptosis and TNF receptor superfamily signaling. Immunol Rev 1999; 169:283–302.PubMedCrossRefGoogle Scholar
  79. 79.
    Xu Y, Cheng G, Baltimore D. Targeted disruption of TRAF3 leads to postnatal lethality and defective T-dependent immune responses. Immunity 1996; 5:407–415.PubMedCrossRefGoogle Scholar
  80. 80.
    Nakano H, Sakon S, Koseki H et al. Targeted disruption of Traf5 gene causes defects in CD40-and CD27-mediated lymphocyte activation. Proc Natl Acad Sci USA 1999; 96:9803–9808.PubMedCrossRefGoogle Scholar
  81. 81.
    Tada K, Okazaki T, Sakon S et al. Critical roles of TRAF2 and TRAF5 in tumor necrosis factor-induced NF-kappa B activation and protection from cell death. J Biol Chem 2001. 276:36530–36534.PubMedCrossRefGoogle Scholar
  82. 82.
    Naito A, Azuma S, Tanaka S et al. Severe osteopetrosis, defective interleukin-1 signalling and lymph node organogenesis in TRAF6-deficient mice. Genes Cells 1999; 4:353–362.PubMedCrossRefGoogle Scholar
  83. 83.
    Walsh MC, Choi Y. Biology of the TRANCE axis. Cytokine Growth Factor Rev 2003; 14:251–263.PubMedCrossRefGoogle Scholar
  84. 84.
    Yoshida H, Naito A, Inoue J et al. Different cytokines induce surface lymphotoxin-alphabeta on IL-7 receptor-alpha cells that differentially engender lymph nodes and Peyer’s patches. Immunity 2002; 17:823–833.PubMedCrossRefGoogle Scholar
  85. 85.
    So T, Salek-Ardakani S, Nakano H et al. TNF receptor-associated factor 5 limits the induction of Th2 immune responses. J Immunol 2004; 172:4292–4297.PubMedGoogle Scholar
  86. 86.
    Anders RA, Subudhi SK, Wang J et al. Contribution of the lymphotoxin beta receptor to liver regeneration. J Immunol 2005; 175:1295–1300.PubMedGoogle Scholar
  87. 87.
    Banks TA, Rickert S, Benedict CA et al. A lymphotoxin-IFN-beta axis essential for lymphocyte survival revealed during cytomegalovirus infection. J Immunol 2005; 174:7217–7225.PubMedGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2007

Authors and Affiliations

  • Paula S. Norris
  • Carl F. Ware
    • 1
  1. 1.Division of Molecular ImmunologyLa Jolla Institute for Allergy and ImmunologySan DiegoUSA

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