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Structural Basis of Death Receptor Signaling

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Cell Death

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Abstract

Death receptors (DRs) initiate formation of intracellular signaling complexes upon stimulation by extracellular ligands to induce apoptosis and necrosis. Here we review the structural information on DR signaling accumulated in the past decade and more. These studies highlight the assembly of oligomeric death domain superfamily complexes in caspase activation in apoptosis and the assembly of a functional amyloid complex in kinase activation in necrosis. They open a new vista for our understanding of intracellular signaling in the DR pathway and other innate and adaptive immune pathways.

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References

  1. Lavrik I, Golks A, Krammer PH. Death receptor signaling. J Cell Sci. 2005;118(Pt 2):265–7.

    Article  PubMed  CAS  Google Scholar 

  2. Banner DW, D’Arcy A, Janes W, Gentz R, Schoenfeld HJ, Broger C, et al. Crystal structure of the soluble human 55 kd TNF receptor-human TNF beta complex: implications for TNF receptor activation. Cell. 1993;73:431–45.

    Article  PubMed  CAS  Google Scholar 

  3. Wu H, Hymowitz SG. Structure and function of tumor necrosis factor (TNF) at the cell surface. In: Bradshaw RA, Dennis EA, editors. Handbook of cell signaling. 2nd ed. Oxford: Academic; 2009. p. 265–75.

    Google Scholar 

  4. Strasser A, Jost PJ, Nagata S. The many roles of FAS receptor signaling in the immune system. Immunity. 2009;30(2):180–92.

    Article  PubMed  CAS  Google Scholar 

  5. Kischkel FC, Hellbardt S, Behrmann I, Germer M, Pawlita M, Krammer PH, et al. Cytotoxicity-dependent APO-1 (Fas/CD95)-associated proteins form a death-inducing signaling complex (DISC) with the receptor. EMBO J. 1995;14(22):5579–88.

    PubMed  CAS  Google Scholar 

  6. Park HH, Lo YC, Lin SC, Wang L, Yang JK, Wu H. The death domain superfamily in intracellular signaling of apoptosis and inflammation. Annu Rev Immunol. 2007;25:561–86.

    Article  PubMed  CAS  Google Scholar 

  7. Ferrao R, Wu H. Helical assembly in the death domain (DD) superfamily. Curr Opin Struct Biol. 2012;22(2):241–7.

    Article  PubMed  CAS  Google Scholar 

  8. Moquin D, Chan FK. The molecular regulation of programmed necrotic cell injury. Trends Biochem Sci. 2010;35(8):434–41.

    Article  PubMed  CAS  Google Scholar 

  9. Walczak H. TNF and ubiquitin at the crossroads of gene activation, cell death, inflammation, and cancer. Immunol Rev. 2011;244(1):9–28.

    Article  PubMed  CAS  Google Scholar 

  10. Wang L, Du F, Wang X. TNF-alpha induces two distinct caspase-8 activation pathways. Cell. 2008;133(4):693–703.

    Article  PubMed  CAS  Google Scholar 

  11. Tenev T, Bianchi K, Darding M, Broemer M, Langlais C, Wallberg F, et al. The ripoptosome, a signaling platform that assembles in response to genotoxic stress and loss of IAPs. Mol Cell. 2011;43(3):432–48.

    Article  PubMed  CAS  Google Scholar 

  12. Feoktistova M, Geserick P, Kellert B, Dimitrova DP, Langlais C, Hupe M, et al. cIAPs block ripoptosome formation, a RIP1/caspase-8 containing intracellular cell death complex differentially regulated by cFLIP isoforms. Mol Cell. 2011;43(3):449–63.

    Article  PubMed  CAS  Google Scholar 

  13. Micheau O, Tschopp J. Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes. Cell. 2003;114(2):181–90.

    Article  PubMed  CAS  Google Scholar 

  14. Huang B, Eberstadt M, Olejniczak ET, Meadows RP, Fesik SW. NMR structure and mutagenesis of the Fas (APO-1/CD95) death domain. Nature. 1996;384(6610):638–41.

    Article  PubMed  CAS  Google Scholar 

  15. Li FY, Jeffrey PD, Yu JW, Shi Y. Crystal structure of a viral FLIP: insights into FLIP-mediated inhibition of death receptor signaling. J Biol Chem. 2006;281(5):2960–8.

    Article  PubMed  CAS  Google Scholar 

  16. Yang JK, Wang L, Zheng L, Wan F, Ahmed M, Lenardo MJ, et al. Crystal structure of MC159 reveals molecular mechanism of DISC assembly and FLIP inhibition. Mol Cell. 2005;20(6):939–49.

    Article  PubMed  CAS  Google Scholar 

  17. Blanchard H, Kodandapani L, Mittl PR, Marco SD, Krebs JF, Wu JC, et al. The three-dimensional structure of caspase-8: an initiator enzyme in apoptosis. Struct Fold Des. 1999;7(9):1125–33.

    Article  CAS  Google Scholar 

  18. Watt W, Koeplinger KA, Mildner AM, Heinrikson RL, Tomasselli AG, Watenpaugh KD. The atomic-resolution structure of human caspase-8, a key activator of apoptosis. Struct Fold Des. 1999;7(9):1135–43.

    Article  CAS  Google Scholar 

  19. Qin H, Srinivasula SM, Wu G, Fernandes-Alnemri T, Alnemri ES, Shi Y. Structural basis of procaspase-9 recruitment by the apoptotic protease-activating factor 1. Nature. 1999;399(6736):549–57.

    Article  PubMed  CAS  Google Scholar 

  20. Xiao T, Towb P, Wasserman SA, Sprang SR. Three-dimensional structure of a complex between the death domains of Pelle and Tube. Cell. 1999;99(5):545–55.

    Article  PubMed  CAS  Google Scholar 

  21. Tinel A, Tschopp J. The PIDDosome, a protein complex implicated in activation of caspase-2 in response to genotoxic stress. Science. 2004;304(5672):843–6.

    Article  PubMed  CAS  Google Scholar 

  22. Tinel A, Janssens S, Lippens S, Cuenin S, Logette E, Jaccard B, et al. Autoproteolysis of PIDD marks the bifurcation between pro-death caspase-2 and pro-survival NF-kappaB pathway. EMBO J. 2006;26:197–208.

    Article  PubMed  Google Scholar 

  23. Janssens S, Tinel A, Lippens S, Tschopp J. PIDD mediates NF-kappaB activation in response to DNA damage. Cell. 2005;123(6):1079–92.

    Article  PubMed  CAS  Google Scholar 

  24. Park HH, Logette E, Rauser S, Cuenin S, Walz T, Tschopp J, et al. Death domain assembly mechanism revealed by crystal structure of the oligomeric PIDDosome core complex. Cell. 2007;128:533–46.

    Article  PubMed  CAS  Google Scholar 

  25. Lin SC, Lo YC, Wu H. Helical assembly in the MyD88-IRAK4-IRAK2 complex in TLR/IL-1R signalling. Nature. 2010;465:885–90.

    Article  PubMed  CAS  Google Scholar 

  26. Wang L, Yang JK, Kabaleeswaran V, Rice AJ, Cruz AC, Park AY, et al. The Fas-FADD death domain complex structure reveals the basis of DISC assembly and disease mutations. Nat Struct Mol Biol. 2010;17:1324–9.

    Article  PubMed  CAS  Google Scholar 

  27. Esposito D, Sankar A, Morgner N, Robinson CV, Rittinger K, Driscoll PC. Solution NMR investigation of the CD95/FADD homotypic death domain complex suggests lack of engagement of the CD95 C terminus. Structure. 2010;18(10):1378–90.

    Article  PubMed  CAS  Google Scholar 

  28. O’Reilly L, Tai L, Lee L, Kruse EA, Grabow S, Fairlie WD, et al. Membrane-bound Fas ligand only is essential for Fas-induced apoptosis. Nature. 2009;461(7264):659–63.

    Article  Google Scholar 

  29. Dhein J, Daniel PT, Trauth BC, Oehm A, Moller P, Krammer PH. Induction of apoptosis by monoclonal antibody anti-APO-1 class switch variants is dependent on cross-linking of APO-1 cell surface antigens. J Immunol. 1992;149(10):3166–73.

    PubMed  CAS  Google Scholar 

  30. Muppidi JR, Siegel RM. Ligand-independent redistribution of Fas (CD95) into lipid rafts mediates clonotypic T cell death. Nat Immunol. 2004;5(2):182–9.

    Article  PubMed  CAS  Google Scholar 

  31. Holler N, Tardivel A, Kovacsovics-Bankowski M, Hertig S, Gaide O, Martinon F, et al. Two adjacent trimeric Fas ligands are required for Fas signaling and formation of a death-inducing signaling complex. Mol Cell Biol. 2003;23(4):1428–40.

    Article  PubMed  CAS  Google Scholar 

  32. Chan FK, Chun HJ, Zheng L, Siegel RM, Bui KL, Lenardo MJ. A domain in TNF receptors that mediates ligand-independent receptor assembly and signaling. Science. 2000;288(5475):2351–4.

    Article  PubMed  CAS  Google Scholar 

  33. Siegel RM, Frederiksen JK, Zacharias DA, Chan FK, Johnson M, Lynch D, et al. Fas preassociation required for apoptosis signaling and dominant inhibition by pathogenic mutations. Science. 2000;288(5475):2354–7.

    Article  PubMed  CAS  Google Scholar 

  34. Mukai Y, Nakamura T, Yoshikawa M, Yoshioka Y, Tsunoda S, Nakagawa S, et al. Solution of the structure of the TNF-TNFR2 complex. Sci Signal. 2010;3(148):ra83.

    Article  PubMed  CAS  Google Scholar 

  35. Wu H. Higher-order assemblies in a new paradigm of signal transduction. Cell. 2013;153(2):287–92.

    Article  PubMed  CAS  Google Scholar 

  36. Dickens LS, Boyd RS, Jukes-Jones R, Hughes MA, Robinson GL, Fairall L, et al. A death effector domain chain DISC model reveals a crucial role for caspase-8 chain assembly in mediating apoptotic cell death. Mol Cell. 2012;47(2):291–305.

    Article  PubMed  CAS  Google Scholar 

  37. Schleich K, Warnken U, Fricker N, Ozturk S, Richter P, Kammerer K, et al. Stoichiometry of the CD95 death-inducing signaling complex: experimental and modeling evidence for a death effector domain chain model. Mol Cell. 2012;47(2):306–19.

    Article  PubMed  CAS  Google Scholar 

  38. Siegel RM, Martin DA, Zheng L, Ng SY, Bertin J, Cohen J, et al. Death-effector filaments: novel cytoplasmic structures that recruit caspases and trigger apoptosis. J Cell Biol. 1998;141(5):1243–53.

    Article  PubMed  CAS  Google Scholar 

  39. Yuan J, Kroemer G. Alternative cell death mechanisms in development and beyond. Genes Dev. 2010;24(23):2592–602.

    Article  PubMed  CAS  Google Scholar 

  40. Galluzzi L, Vitale I, Abrams JM, Alnemri ES, Baehrecke EH, Blagosklonny MV, et al. Molecular definitions of cell death subroutines: recommendations of the Nomenclature Committee on Cell Death 2012. Cell Death Differ. 2012;19(1):107–20.

    Article  PubMed  CAS  Google Scholar 

  41. Han J, Zhong CQ, Zhang DW. Programmed necrosis: backup to and competitor with apoptosis in the immune system. Nat Immunol. 2011;12(12):1143–9.

    Article  PubMed  CAS  Google Scholar 

  42. Vandenabeele P, Galluzzi L, Vanden Berghe T, Kroemer G. Molecular mechanisms of necroptosis: an ordered cellular explosion. Nat Rev Mol Cell Biol. 2010;11(10):700–14.

    Article  PubMed  CAS  Google Scholar 

  43. Kaiser WJ, Upton JW, Long AB, Livingston-Rosanoff D, Daley-Bauer LP, Hakem R, et al. RIP3 mediates the embryonic lethality of caspase-8-deficient mice. Nature. 2011;471(7338):368–72.

    Article  PubMed  CAS  Google Scholar 

  44. Oberst A, Dillon CP, Weinlich R, McCormick LL, Fitzgerald P, Pop C, et al. Catalytic activity of the caspase-8-FLIP(L) complex inhibits RIPK3-dependent necrosis. Nature. 2011;471(7338):363–7.

    Article  PubMed  CAS  Google Scholar 

  45. Welz PS, Wullaert A, Vlantis K, Kondylis V, Fernandez-Majada V, Ermolaeva M, et al. FADD prevents RIP3-mediated epithelial cell necrosis and chronic intestinal inflammation. Nature. 2011;477:330–4. doi:10.1038/nature10273.

    Article  PubMed  CAS  Google Scholar 

  46. Zhang H, Zhou X, McQuade T, Li J, Chan FK, Zhang J. Functional complementation between FADD and RIP1 in embryos and lymphocytes. Nature. 2011;471(7338):373–6.

    Article  PubMed  CAS  Google Scholar 

  47. Lin Y, Devin A, Rodriguez Y, Liu ZG. Cleavage of the death domain kinase RIP by caspase-8 prompts TNF-induced apoptosis. Genes Dev. 1999;13(19):2514–26.

    Article  PubMed  CAS  Google Scholar 

  48. Chan FK, Shisler J, Bixby JG, Felices M, Zheng L, Appel M, et al. A role for tumor necrosis factor receptor-2 and receptor-interacting protein in programmed necrosis and antiviral responses. J Biol Chem. 2003;278(51):51613–21.

    Article  PubMed  CAS  Google Scholar 

  49. Feng S, Yang Y, Mei Y, Ma L, Zhu DE, Hoti N, et al. Cleavage of RIP3 inactivates its caspase-independent apoptosis pathway by removal of kinase domain. Cell Signal. 2007;19(10):2056–67.

    Article  PubMed  CAS  Google Scholar 

  50. Cho YS, Challa S, Moquin D, Genga R, Ray TD, Guildford M, et al. Phosphorylation-driven assembly of the RIP1-RIP3 complex regulates programmed necrosis and virus-induced inflammation. Cell. 2009;137(6):1112–23.

    Article  PubMed  CAS  Google Scholar 

  51. He S, Wang L, Miao L, Wang T, Du F, Zhao L, et al. Receptor interacting protein kinase-3 determines cellular necrotic response to TNF-alpha. Cell. 2009;137(6):1100–11.

    Article  PubMed  CAS  Google Scholar 

  52. Zhang DW, Shao J, Lin J, Zhang N, Lu BJ, Lin SC, et al. RIP3, an energy metabolism regulator that switches TNF-induced cell death from apoptosis to necrosis. Science. 2009;325:332–6.

    Article  PubMed  CAS  Google Scholar 

  53. Stanger BZ, Leder P, Lee T, Kim E, Seed B. RIP: a novel protein containing a death domain that interacts with Fas/APO-1 (CD95) in yeast and causes cell death. Cell. 1995;81:513–23.

    Article  PubMed  CAS  Google Scholar 

  54. Sun X, Lee J, Navas T, Baldwin DT, Stewart TA, Dixit VM. RIP3, a novel apoptosis-inducing kinase. J Biol Chem. 1999;274(24):16871–5.

    Article  PubMed  CAS  Google Scholar 

  55. Li J, McQuade T, Siemer AB, Napetschnig J, Moriwaki K, Hsiao YS, et al. The RIP1/RIP3 necrosome forms a functional amyloid signaling complex required for programmed necrosis. Cell. 2012;150:339–50.

    Article  PubMed  CAS  Google Scholar 

  56. Sun X, Yin J, Starovasnik MA, Fairbrother WJ, Dixit VM. Identification of a novel homotypic interaction motif required for the phosphorylation of receptor-interacting protein (RIP) by RIP3. J Biol Chem. 2002;277(11):9505–11.

    Article  PubMed  CAS  Google Scholar 

  57. Chiti F, Dobson CM. Protein misfolding, functional amyloid, and human disease. Annu Rev Biochem. 2006;75:333–66.

    Article  PubMed  CAS  Google Scholar 

  58. Balbirnie M, Grothe R, Eisenberg DS. An amyloid-forming peptide from the yeast prion Sup35 reveals a dehydrated beta-sheet structure for amyloid. Proc Natl Acad Sci U S A. 2001;98(5):2375–80.

    Article  PubMed  CAS  Google Scholar 

  59. Eisenberg D, Jucker M. The amyloid state of proteins in human diseases. Cell. 2012;148(6):1188–203.

    Article  PubMed  CAS  Google Scholar 

  60. Sun L, Wang H, Wang Z, He S, Chen S, Liao D, et al. Mixed lineage kinase domain-like protein mediates necrosis signaling downstream of RIP3 kinase. Cell. 2012;148(1–2):213–27.

    Article  PubMed  CAS  Google Scholar 

  61. Wang Z, Jiang H, Chen S, Du F, Wang X. The mitochondrial phosphatase PGAM5 functions at the convergence point of multiple necrotic death pathways. Cell. 2012;148(1–2):228–43.

    Article  PubMed  CAS  Google Scholar 

  62. Zhao J, Jitkaew S, Cai Z, Choksi S, Li Q, Luo J, et al. Mixed lineage kinase domain-like is a key receptor interacting protein 3 downstream component of TNF-induced necrosis. Proc Natl Acad Sci U S A. 2012;109:5322–7.

    Article  PubMed  CAS  Google Scholar 

  63. Bettinardi A, Brugnoni D, Quiros-Roldan E, Malagoli A, La Grutta S, Correra A, et al. Missense mutations in the Fas gene resulting in autoimmune lymphoproliferative syndrome: a molecular and immunological analysis. Blood. 1997;89(3):902–9.

    PubMed  CAS  Google Scholar 

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Acknowledgment

We thank for the funding support from the National Institutes of Health (to HW).

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Authors and Affiliations

  1. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, 02115, USA

    Jixi Li Ph.D. & Hao Wu Ph.D.

  2. Program in Cellular and Molecular Medicine, Boston Children’s Hospital, Boston, MA, 02115, USA

    Jixi Li Ph.D. & Hao Wu Ph.D.

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  1. Jixi Li Ph.D.
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  2. Hao Wu Ph.D.
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Correspondence to Hao Wu Ph.D. .

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  1. Dept. of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA

    Hao Wu

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Li, J., Wu, H. (2014). Structural Basis of Death Receptor Signaling. In: Wu, H. (eds) Cell Death. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-9302-0_12

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