Skip to main content
Log in

Tandem DEDs and CARDs suggest novel mechanisms of signaling complex assembly

  • The Domains of Apoptosis and Inflammation
  • Published:
Apoptosis Aims and scope Submit manuscript

Abstract

Apoptosis is an important process to maintain cellular homeostasis. Deregulated apoptosis has linked to a number of diseases, such as inflammatory diseases, neurodegenerative disorder, and cancers. A major signaling complex in the death receptor signaling pathway leading to apoptosis is death-induced signaling complex (DISC), which is regulated mainly by death effector domain (DED)-containing proteins. There are seven DED-containing proteins in human, including FADD, c-FLIP, caspase-8, caspase-10, DEDD, DEDD2, and PEA-15. The main players in DISC formation employ tandem DEDs for regulating signaling complex formation. The regulatory mechanism of signaling complex formation is important and yet remains unclear. Interestingly, three caspase recruitment domain (CARD)-containing members, which belong to the same DD superfamily as DED-containing proteins, also contains similar tandem CARDs. Recent structural studies have shown that tandem CARDs are essential for the formation of a helical signaling complex. This review summarizes recent structural studies on DED-containing proteins and especially discusses the studies on tandem DEDs and tandem CARDs, which suggest new mechanisms of signaling complex assembly.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100:57–70

    Article  CAS  PubMed  Google Scholar 

  2. Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674

    Article  CAS  PubMed  Google Scholar 

  3. Green DR, Evan GI (2002) A matter of life and death. Cancer Cell 1:19–30

    Article  CAS  PubMed  Google Scholar 

  4. Vaux DL, Korsmeyer SJ (1999) Cell death in development. Cell 96:245–254

    Article  CAS  PubMed  Google Scholar 

  5. Mattson MP (2000) Apoptosis in neurodegenerative disorders. Nat Rev Mol Cell Biol 1:120–129

    Article  CAS  PubMed  Google Scholar 

  6. Ramaswamy M, Deng M, Siegel RM (2011) Harnessing programmed cell death as a therapeutic strategy in rheumatic diseases. Nat Rev Rheumatol 7:152–160

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Reed JC, Doctor KS, Godzik A (2004) The domains of apoptosis: a genomics perspective. Sci STKE 239:re9

    Google Scholar 

  8. Dempsey PW, Doyle SE, He JQ, Cheng G (2003) The signaling adaptors and pathways activated by TNF superfamily. Cytokine Growth Factor Rev 14:193–209

    Article  CAS  PubMed  Google Scholar 

  9. Kischkel FC, Lawrence DA, Chuntharapai A, Schow P, Kim KJ, Ashkenazi A (2000) Apo2L/TRAIL-dependent recruitment of endogenous FADD and caspase-8 to death receptors 4 and 5. Immunity 12:611–620

    Article  CAS  PubMed  Google Scholar 

  10. Holler N, Tardivel A, Kovacsovics-Bankowski M et al (2003) Two adjacent trimeric Fas ligands are required for Fas signaling and formation of a death-inducing signaling complex. Mol Cell Biol 23:1428–1440

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Scott FL, Stec B, Pop C et al (2009) The Fas-FADD death domain complex structure unravels signalling by receptor clustering. Nature 457:1019–1022

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Peter ME, Krammer PH (2003) The CD95(APO-1/Fas) DISC and beyond. Cell Death Differ 10:26–35

    Article  CAS  PubMed  Google Scholar 

  13. Bao Q, Shi Y (2007) Apoptosome: a platform for the activation of initiator caspases. Cell Death Differ 14:56–65

    Article  CAS  PubMed  Google Scholar 

  14. Fuentes-Prior P, Salvesen GS (2004) The protein structures that shape caspase activity, specificity, activation and inhibition. Biochem J 384:201–232

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Riedl SJ, Shi Y (2004) Molecular mechanisms of caspase regulation during apoptosis. Nat Rev Mol Cell Biol 5:897–907

    Article  CAS  PubMed  Google Scholar 

  16. Weber CH, Vincenz C (2001) The death domain superfamily: a tale of two interfaces? Trends Biochem Sci 26:475–481

    Article  CAS  PubMed  Google Scholar 

  17. Park HH, Lo YC, Lin SC, Wang L, Yang JK, Wu H (2007) The death domain superfamily in intracellular signaling of apoptosis and inflammation. Annu Rev Immunol 25:561–586

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Chinnaiyan AM, O’Rourke K, Tewari M, Dixit VM (1995) FADD, a novel death domain-containing protein, interacts with the death domain of Fas and initiates apoptosis. Cell 81:505–512

    Article  CAS  PubMed  Google Scholar 

  19. Kischkel FC, Hellbardt S, Behrmann I et al (1995) Cytotoxicity-dependent APO-1 (Fas/CD95)-associated proteins form a death-inducing signaling complex (DISC) with the receptor. EMBO J 14:5579–5588

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Boldin MP, Goncharov TM, Goltsev YV, Wallach D (1996) Involvement of MACH, a novel MORT1/FADD-interacting protease, in Fas/APO-1- and TNF receptor-induced cell death. Cell 85:803–815

    Article  CAS  PubMed  Google Scholar 

  21. Muzio M, Chinnaiyan AM, Kischkel FC et al (1996) FLICE, a novel FADD-homologous ICE/CED-3-like protease, is recruited to the CD95 (Fas/APO-1) death–inducing signaling complex. Cell 85:817–827

    Article  CAS  PubMed  Google Scholar 

  22. Shi Y (2004) Caspase activation: revisiting the induced proximity model. Cell 117:855–858

    Article  CAS  PubMed  Google Scholar 

  23. Medema JP, Scaffidi C, Kischkel FC et al (1997) FLICE is activated by association with the CD95 death-inducing signaling complex (DISC). EMBO J 16:2794–2804

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Salvesen GS, Dixit VM (1999) Caspase activation: the induced-proximity model. Proc Natl Acad Sci USA 96:10964–10967

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Thome M, Schneider P, Hofmann K et al (1997) Viral FLICE-inhibitory proteins (FLIPs) prevent apoptosis induced by death receptors. Nature 386:517–521

    Article  CAS  PubMed  Google Scholar 

  26. Thome M, Tschopp J (2001) Regulation of lymphocyte proliferation and death by FLIP. Nat Rev Immunol 1:50–58

    Article  CAS  PubMed  Google Scholar 

  27. Searles RP, Bergquam EP, Axthelm MK, Wong SW (1999) Sequence and genomic analysis of a Rhesus macaque rhadinovirus with similarity to Kaposi’s sarcoma-associated herpesvirus/human herpesvirus 8. J Virol 73:3040–3053

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Hu S, Vincenz C, Buller M, Dixit VM (1997) A novel family of viral death effector domain-containing molecules that inhibit both CD-95- and tumor necrosis factor receptor-1-induced apoptosis. J Biol Chem 272:9621–9624

    Article  CAS  PubMed  Google Scholar 

  29. Bertin J, Armstrong RC, Ottilie S et al (1997) Death effector domain-containing herpesvirus and poxvirus proteins inhibit both Fas- and TNFR1-induced apoptosis. Proc Natl Acad Sci USA 94:1172–1176

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Irmler M, Thome M, Hahne M et al (1997) Inhibition of death receptor signals by cellular FLIP. Nature 388:190–195

    Article  CAS  PubMed  Google Scholar 

  31. Golks A, Brenner D, Fritsch C, Krammer PH, Lavrik IN (2005) c-FLIPR, a new regulator of death receptor-induced apoptosis. J Biol Chem 280:14507–14513

    Article  CAS  PubMed  Google Scholar 

  32. Safa AR (2012) c-FLIP, a master anti-apoptotic regulator. Exp Oncol 34:176–184

    CAS  PubMed  Google Scholar 

  33. Ozturk S, Schleich K, Lavrik IN (2012) Cellular FLICE-like inhibitory proteins (c-FLIPs): fine-tuners of life and death decisions. Exp Cell Res 318:1324–1331

    Article  CAS  PubMed  Google Scholar 

  34. Han DK, Chaudhary PM, Wright ME et al (1997) MRIT, a novel death-effector domain-containing protein, interacts with caspases and BclXL and initiates cell death. Proc Natl Acad Sci USA 94:11333–11338

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Goltsev YV, Kovalenko AV, Arnold E, Varfolomeev EE, Brodianskii VM, Wallach D (1997) CASH, a novel caspase homologue with death effector domains. J Biol Chem 272:19641–19644

    Article  CAS  PubMed  Google Scholar 

  36. Rasper DM, Vaillancourt JP, Hadano S et al (1998) Cell death attenuation by ‘Usurpin’, a mammalian DED-caspase homologue that precludes caspase-8 recruitment and activation by the CD-95 (Fas, APO-1) receptor complex. Cell Death Differ 5:271–288

    Article  CAS  PubMed  Google Scholar 

  37. Inohara N, Koseki T, Hu Y, Chen S, Nunez G (1997) CLARP, a death effector domain-containing protein interacts with caspase-8 and regulates apoptosis. Proc Natl Acad Sci USA 94:10717–10722

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Srinivasula SM, Ahmad M, Ottilie S et al (1997) FLAME-1, a novel FADD-like anti-apoptotic molecule that regulates Fas/TNFR1-induced apoptosis. J Biol Chem 272:18542–18545

    Article  CAS  PubMed  Google Scholar 

  39. Matta H, Chaudhary PM (2004) Activation of alternative NF-kappa B pathway by human herpes virus 8-encoded Fas-associated death domain-like IL-1 beta-converting enzyme inhibitory protein (vFLIP). Proc Natl Acad Sci USA 101:9399–9404

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Desbarats J, Birge RB, Mimouni-Rongy M, Weinstein DE, Palerme JS, Newell MK (2003) Fas engagement induces neurite growth through ERK activation and p35 upregulation. Nat Cell Biol 5:118–125

    Article  CAS  PubMed  Google Scholar 

  41. Schneider P, Thome M, Burns K et al (1997) TRAIL receptors 1 (DR4) and 2 (DR5) signal FADD-dependent apoptosis and activate NF-kappaB. Immunity 7:831–836

    Article  CAS  PubMed  Google Scholar 

  42. Neumann L, Pforr C, Beaudouin J et al (2010) Dynamics within the CD95 death-inducing signaling complex decide life and death of cells. Mol Syst Biol 6:352

    Article  PubMed  PubMed Central  Google Scholar 

  43. Kataoka T, Budd RC, Holler N et al (2000) The caspase-8 inhibitor FLIP promotes activation of NF-kappaB and Erk signaling pathways. Curr Biol 10:640–648

    Article  CAS  PubMed  Google Scholar 

  44. Kreuz S, Siegmund D, Rumpf JJ et al (2004) NFkappaB activation by Fas is mediated through FADD, caspase-8, and RIP and is inhibited by FLIP. J Cell Biol 166:369–380

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Djerbi M, Darreh-Shori T, Zhivotovsky B, Grandien A (2001) Characterization of the human FLICE-inhibitory protein locus and comparison of the anti-apoptotic activity of four different flip isoforms. Scand J Immunol 54:180–189

    Article  CAS  PubMed  Google Scholar 

  46. Schickling O, Stegh AH, Byrd J, Peter ME (2001) Nuclear localization of DEDD leads to caspase-6 activation through its death effector domain and inhibition of RNA polymerase I dependent transcription. Cell Death Differ 8:1157–1168

    Article  CAS  PubMed  Google Scholar 

  47. Roth W, Stenner-Liewen F, Pawlowski K, Godzik A, Reed JC (2002) Identification and characterization of DEDD2, a death effector domain-containing protein. J Biol Chem 277:7501–7508

    Article  CAS  PubMed  Google Scholar 

  48. Lv Q, Wang W, Xue J et al (2012) DEDD interacts with PI3KC3 to activate autophagy and attenuate epithelial-mesenchymal transition in human breast cancer. Cancer Res 72:3238–3250

    Article  CAS  PubMed  Google Scholar 

  49. Sharif A, Canton B, Junier MP, Chneiweiss H (2003) PEA-15 modulates TNFalpha intracellular signaling in astrocytes. Ann NY Acad Sci 1010:43–50

    Article  CAS  PubMed  Google Scholar 

  50. Fiory F, Formisano P, Perruolo G, Beguinot F (2009) Frontiers: PED/PEA-15, a multifunctional protein controlling cell survival and glucose metabolism. Am J Physiol Endocrinol Metab 297:E592–E601

    Article  CAS  PubMed  Google Scholar 

  51. Garvey T, Bertin J, Siegel R, Lenardo M, Cohen J (2002) The death effector domains (DEDs) of the molluscum contagiosum virus MC159 v-FLIP protein are not functionally interchangeable with each other or with the DEDs of caspase-8. Virology 300:217–225

    Article  CAS  PubMed  Google Scholar 

  52. Eberstadt M, Huang B, Chen Z et al (1998) NMR structure and mutagenesis of the FADD (Mort1) death-effector domain. Nature 392:941–945

    Article  CAS  PubMed  Google Scholar 

  53. Hill JM, Vaidyanathan H, Ramos JW, Ginsberg MH, Werner MH (2002) Recognition of ERK MAP kinase by PEA-15 reveals a common docking site within the death domain and death effector domain. EMBO J 21:6494–6504

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Twomey EC, Wei Y (2012) High-definition NMR structure of PED/PEA-15 death effector domain reveals details of key polar side chain interactions. Biochem Biophys Res Commun 424:141–146

    Article  CAS  PubMed  Google Scholar 

  55. Yang JK, Wang L, Zheng L et al (2005) Crystal structure of MC159 reveals molecular mechanism of DISC assembly and FLIP inhibition. Mol Cell 20:939–949

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Bagneris C, Ageichik AV, Cronin N et al (2008) Crystal structure of a vFlip-IKKgamma complex: insights into viral activation of the IKK signalosome. Mol Cell 30:620–631

    Article  CAS  PubMed  Google Scholar 

  57. Mace PD, Wallez Y, Egger MF et al (2013) Structure of ERK2 bound to PEA-15 reveals a mechanism for rapid release of activated MAPK. Nat Commun 4:1681

    Article  PubMed  PubMed Central  Google Scholar 

  58. Arnold K, Bordoli L, Kopp J, Schwede T (2006) The SWISS-MODEL workspace: a web-based environment for protein structure homology modelling. Bioinformatics 22:195–201

    Article  CAS  PubMed  Google Scholar 

  59. Park HH, Logette E, Raunser S et al (2007) Death domain assembly mechanism revealed by crystal structure of the oligomeric PIDDosome core complex. Cell 128:533–546

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Lin SC, Lo YC, Wu H (2010) Helical assembly in the MyD88-IRAK4-IRAK2 complex in TLR/IL-1R signalling. Nature 465:885–890

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Wu B, Peisley A, Tetrault D et al (2014) Molecular Imprinting as a Signal-Activation Mechanism of the Viral RNA Sensor RIG-I. Mol Cell 55:511–523

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Schleich K, Warnken U, Fricker N et al (2012) Stoichiometry of the CD95 death-inducing signaling complex: experimental and modeling evidence for a death effector domain chain model. Mol Cell 47:306–319

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work is supported by Ministry of Science and Technology Grant MOST 101-2311-B-006-008-MY3 and Academia Sinica Thematic Research Program AS-102-TP-B14-1 (to Y.C.L.), and Ministry of Science and Technology Grant MOST 101-2320-B-001-034-MY3 and Academia Sinica Thematic Research Program AS-102-TP-B14-2 (to S.C.L.), and Academia Sinica Postdoc Fellowship (to C.Y.Y.).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Yu-Chih Lo.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lo, YC., Lin, SC., Yang, CY. et al. Tandem DEDs and CARDs suggest novel mechanisms of signaling complex assembly. Apoptosis 20, 124–135 (2015). https://doi.org/10.1007/s10495-014-1054-4

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10495-014-1054-4

Keywords

Navigation