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Developmental checkpoints guarded by regulated necrosis

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Abstract

The process of embryonic development is highly regulated through the symbiotic control of differentiation and programmed cell death pathways, which together sculpt tissues and organs. The importance of programmed necrotic (RIPK-dependent necroptosis) cell death during development has recently been recognized as important and has largely been characterized using genetically engineered animals. Suppression of necroptosis appears to be essential for murine development and occurs at three distinct checkpoints, E10.5, E16.5, and P1. These distinct time points have helped delineate the molecular pathways and regulation of necroptosis. The embryonic lethality at E10.5 seen in knockouts of caspase-8, FADD, or FLIP (cflar), components of the extrinsic apoptosis pathway, resulted in pallid embryos that did not exhibit the expected cellular expansions. This was the first suggestion that these factors play an important role in the inhibition of necroptotic cell death. The embryonic lethality at E16.5 highlighted the importance of TNF engaging necroptosis in vivo, since elimination of TNFR1 from casp8 −/−, fadd −/−, or cflar −/−, ripk3 −/− embryos delayed embryonic lethality from E10.5 until E16.5. The P1 checkpoint demonstrates the dual role of RIPK1 in both the induction and inhibition of necroptosis, depending on the upstream signal. This review summarizes the role of necroptosis in development and the genetic evidence that helped detail the molecular mechanisms of this novel pathway of programmed cell death.

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References

  1. Green DR, Llambi F (2015) Cell Death Signaling. Cold Spring Harb Perspect Biol 7(12). doi:10.1101/cshperspect.a006080

  2. Cecconi F, Alvarez-Bolado G, Meyer BI, Roth KA, Gruss P (1998) Apaf1 (CED-4 homolog) regulates programmed cell death in mammalian development. Cell 94(6):727–737

    Article  CAS  PubMed  Google Scholar 

  3. Yoshida H, Kong YY, Yoshida R, Elia AJ, Hakem A, Hakem R, Penninger JM, Mak TW (1998) Apaf1 is required for mitochondrial pathways of apoptosis and brain development. Cell 94(6):739–750

    Article  CAS  PubMed  Google Scholar 

  4. Lindsten T, Ross AJ, King A, Zong WX, Rathmell JC, Shiels HA, Ulrich E, Waymire KG, Mahar P, Frauwirth K, Chen Y, Wei M, Eng VM, Adelman DM, Simon MC, Ma A, Golden JA, Evan G, Korsmeyer SJ, MacGregor GR, Thompson CB (2000) The combined functions of proapoptotic Bcl-2 family members bak and bax are essential for normal development of multiple tissues. Mol Cell 6(6):1389–1399

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Varfolomeev EE, Schuchmann M, Luria V, Chiannilkulchai N, Beckmann JS, Mett IL, Rebrikov D, Brodianski VM, Kemper OC, Kollet O, Lapidot T, Soffer D, Sobe T, Avraham KB, Goncharov T, Holtmann H, Lonai P, Wallach D (1998) Targeted disruption of the mouse Caspase 8 gene ablates cell death induction by the TNF receptors, Fas/Apo1, and DR3 and is lethal prenatally. Immunity 9(2):267–276

    Article  CAS  PubMed  Google Scholar 

  6. Yeh WC, de la Pompa JL, McCurrach ME, Shu HB, Elia AJ, Shahinian A, Ng M, Wakeham A, Khoo W, Mitchell K, El-Deiry WS, Lowe SW, Goeddel DV, Mak TW (1998) FADD: essential for embryo development and signaling from some, but not all, inducers of apoptosis. Science 279(5358):1954–1958

    Article  CAS  PubMed  Google Scholar 

  7. Yeh WC, Itie A, Elia AJ, Ng M, Shu HB, Wakeham A, Mirtsos C, Suzuki N, Bonnard M, Goeddel DV, Mak TW (2000) Requirement for Casper (c-FLIP) in regulation of death receptor-induced apoptosis and embryonic development. Immunity 12(6):633–642

    Article  CAS  PubMed  Google Scholar 

  8. Zhang J, Winoto A (1996) A mouse Fas-associated protein with homology to the human Mort1/FADD protein is essential for Fas-induced apoptosis. Mol Cell Biol 16(6):2756–2763

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Vercammen D, Beyaert R, Denecker G, Goossens V, Van Loo G, Declercq W, Grooten J, Fiers W, Vandenabeele P (1998) Inhibition of caspases increases the sensitivity of L929 cells to necrosis mediated by tumor necrosis factor. J Exp Med 187(9):1477–1485

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Green DR, Oberst A, Dillon CP, Weinlich R, Salvesen GS (2011) RIPK-dependent necrosis and its regulation by caspases: a mystery in five acts. Mol Cell 44(1):9–16. doi:10.1016/j.molcel.2011.09.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Weinlich R, Dillon CP, Green DR (2011) Ripped to death. Trends Cell Biol 21(11):630–637. doi:10.1016/j.tcb.2011.09.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Vanden Berghe T, Linkermann A, Jouan-Lanhouet S, Walczak H, Vandenabeele P (2014) Regulated necrosis: the expanding network of non-apoptotic cell death pathways. Nat Rev Mol Cell Biol 15(2):135–147. doi:10.1038/nrm3737

    Article  CAS  PubMed  Google Scholar 

  13. Holler N, Zaru R, Micheau O, Thome M, Attinger A, Valitutti S, Bodmer JL, Schneider P, Seed B, Tschopp J (2000) Fas triggers an alternative, caspase-8-independent cell death pathway using the kinase RIP as effector molecule. Nat Immunol 1(6):489–495. doi:10.1038/82732

    Article  CAS  PubMed  Google Scholar 

  14. Zhang DW, Shao J, Lin J, Zhang N, Lu BJ, Lin SC, Dong MQ, Han J (2009) RIP3, an energy metabolism regulator that switches TNF-induced cell death from apoptosis to necrosis. Science 325(5938):332–336. doi:10.1126/science.1172308

    Article  CAS  PubMed  Google Scholar 

  15. Cho YS, Challa S, Moquin D, Genga R, Ray TD, Guildford M, Chan FK (2009) Phosphorylation-driven assembly of the RIP1-RIP3 complex regulates programmed necrosis and virus-induced inflammation. Cell 137(6):1112–1123. doi:10.1016/j.cell.2009.05.037

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Brenner D, Blaser H, Mak TW (2015) Regulation of tumour necrosis factor signalling: live or let die. Nat Rev Immunol 15(6):362–374. doi:10.1038/nri3834

    Article  CAS  PubMed  Google Scholar 

  17. Justus SJ, Ting AT (2015) Cloaked in ubiquitin, a killer hides in plain sight: the molecular regulation of RIPK1. Immunol Rev 266(1):145–160. doi:10.1111/imr.12304

    Article  CAS  PubMed  Google Scholar 

  18. Linkermann A, Green DR (2014) Necroptosis. N Engl J Med 370(5):455–465. doi:10.1056/NEJMra1310050

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Sun X, Yin J, Starovasnik MA, Fairbrother WJ, Dixit VM (2002) Identification of a novel homotypic interaction motif required for the phosphorylation of receptor-interacting protein (RIP) by RIP3. J Biol Chem 277(11):9505–9511. doi:10.1074/jbc.M109488200

    Article  CAS  PubMed  Google Scholar 

  20. Weinlich R, Green DR (2014) The two faces of receptor interacting protein kinase-1. Mol Cell 56(4):469–480. doi:10.1016/j.molcel.2014.11.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Silke J, Rickard JA, Gerlic M (2015) The diverse role of RIP kinases in necroptosis and inflammation. Nat Immunol 16(7):689–697. doi:10.1038/ni.3206

    Article  CAS  PubMed  Google Scholar 

  22. Dondelinger Y, Declercq W, Montessuit S, Roelandt R, Goncalves A, Bruggeman I, Hulpiau P, Weber K, Sehon CA, Marquis RW, Bertin J, Gough PJ, Savvides S, Martinou JC, Bertrand MJ, Vandenabeele P (2014) MLKL compromises plasma membrane integrity by binding to phosphatidylinositol phosphates. Cell Rep 7(4):971–981. doi:10.1016/j.celrep.2014.04.026

    Article  CAS  PubMed  Google Scholar 

  23. Galluzzi L, Kepp O, Kroemer G (2014) MLKL regulates necrotic plasma membrane permeabilization. Cell Res 24(2):139–140. doi:10.1038/cr.2014.8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Hildebrand JM, Tanzer MC, Lucet IS, Young SN, Spall SK, Sharma P, Pierotti C, Garnier JM, Dobson RC, Webb AI, Tripaydonis A, Babon JJ, Mulcair MD, Scanlon MJ, Alexander WS, Wilks AF, Czabotar PE, Lessene G, Murphy JM, Silke J (2014) Activation of the pseudokinase MLKL unleashes the four-helix bundle domain to induce membrane localization and necroptotic cell death. Proc Natl Acad Sci USA 111(42):15072–15077. doi:10.1073/pnas.1408987111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Murphy JM, Czabotar PE, Hildebrand JM, Lucet IS, Zhang JG, Alvarez-Diaz S, Lewis R, Lalaoui N, Metcalf D, Webb AI, Young SN, Varghese LN, Tannahill GM, Hatchell EC, Majewski IJ, Okamoto T, Dobson RC, Hilton DJ, Babon JJ, Nicola NA, Strasser A, Silke J, Alexander WS (2013) The pseudokinase MLKL mediates necroptosis via a molecular switch mechanism. Immunity 39(3):443–453. doi:10.1016/j.immuni.2013.06.018

    Article  CAS  PubMed  Google Scholar 

  26. Rodriguez DA, Weinlich R, Brown S, Guy C, Fitzgerald P, Dillon CP, Oberst A, Quarato G, Low J, Cripps JG, Chen T, Green DR (2015) Characterization of RIPK3-mediated phosphorylation of the activation loop of MLKL during necroptosis. Cell Death Differ. doi:10.1038/cdd.2015.70

    Google Scholar 

  27. Shin YK, Kim J, Yang Y (2014) Switch for the necroptotic permeation pore. Structure 22(10):1374–1376. doi:10.1016/j.str.2014.09.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Su L, Quade B, Wang H, Sun L, Wang X, Rizo J (2014) A plug release mechanism for membrane permeation by MLKL. Structure 22(10):1489–1500. doi:10.1016/j.str.2014.07.014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Quarato G, Guy CS, Grace CR, Llambi F, Nourse A, Rodriguez DA, Wakefield R, Frase S, Moldoveanu T, Green DR (2016) Sequential engagement of distinct MLKL phosphatidylinositol-binding sites executes necroptosis. Mol Cell. doi:10.1016/j.molcel.2016.01.011

    PubMed  Google Scholar 

  30. Oberst A, Green DR (2011) It cuts both ways: reconciling the dual roles of caspase 8 in cell death and survival. Nat Rev Mol Cell Biol 12(11):757–763. doi:10.1038/nrm3214

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Oberst A, Dillon CP, Weinlich R, McCormick LL, Fitzgerald P, Pop C, Hakem R, Salvesen GS, Green DR (2011) Catalytic activity of the caspase-8-FLIP(L) complex inhibits RIPK3-dependent necrosis. Nature 471(7338):363–367. doi:10.1038/nature09852

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Dillon CP, Oberst A, Weinlich R, Janke LJ, Kang TB, Ben-Moshe T, Mak TW, Wallach D, Green DR (2012) Survival function of the FADD-CASPASE-8-cFLIP(L) complex. Cell Rep 1(5):401–407. doi:10.1016/j.celrep.2012.03.010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Kaiser WJ, Upton JW, Long AB, Livingston-Rosanoff D, Daley-Bauer LP, Hakem R, Caspary T, Mocarski ES (2011) RIP3 mediates the embryonic lethality of caspase-8-deficient mice. Nature 471(7338):368–372. doi:10.1038/nature09857

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. O’Donnell MA, Perez-Jimenez E, Oberst A, Ng A, Massoumi R, Xavier R, Green DR, Ting AT (2011) Caspase 8 inhibits programmed necrosis by processing CYLD. Nat Cell Biol 13(12):1437–1442. doi:10.1038/ncb2362

    Article  PubMed  PubMed Central  Google Scholar 

  35. Thapa RJ, Nogusa S, Chen P, Maki JL, Lerro A, Andrake M, Rall GF, Degterev A, Balachandran S (2013) Interferon-induced RIP1/RIP3-mediated necrosis requires PKR and is licensed by FADD and caspases. Proc Natl Acad Sci USA 110(33):E3109–E3118. doi:10.1073/pnas.1301218110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Kaiser WJ, Sridharan H, Huang C, Mandal P, Upton JW, Gough PJ, Sehon CA, Marquis RW, Bertin J, Mocarski ES (2013) Toll-like receptor 3-mediated necrosis via TRIF, RIP3, and MLKL. J Biol Chem 288(43):31268–31279. doi:10.1074/jbc.M113.462341

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Dillon CP, Weinlich R, Rodriguez DA, Cripps JG, Quarato G, Gurung P, Verbist KC, Brewer TL, Llambi F, Gong YN, Janke LJ, Kelliher MA, Kanneganti TD, Green DR (2014) RIPK1 blocks early postnatal lethality mediated by caspase-8 and RIPK3. Cell 157(5):1189–1202. doi:10.1016/j.cell.2014.04.018

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Weinlich R, Oberst A, Dillon CP, Janke LJ, Milasta S, Lukens JR, Rodriguez DA, Gurung P, Savage C, Kanneganti TD, Green DR (2013) Protective roles for caspase-8 and cFLIP in adult homeostasis. Cell Rep 5(2):340–348. doi:10.1016/j.celrep.2013.08.045

    Article  CAS  PubMed  Google Scholar 

  39. Sakamaki K, Inoue T, Asano M, Sudo K, Kazama H, Sakagami J, Sakata S, Ozaki M, Nakamura S, Toyokuni S, Osumi N, Iwakura Y, Yonehara S (2002) Ex vivo whole-embryo culture of caspase-8-deficient embryos normalize their aberrant phenotypes in the developing neural tube and heart. Cell Death Differ 9(11):1196–1206. doi:10.1038/sj.cdd.4401090

    Article  CAS  PubMed  Google Scholar 

  40. Kang TB, Oh GS, Scandella E, Bolinger B, Ludewig B, Kovalenko A, Wallach D (2008) Mutation of a self-processing site in caspase-8 compromises its apoptotic but not its nonapoptotic functions in bacterial artificial chromosome-transgenic mice. J Immunol 181(4):2522–2532

    Article  CAS  PubMed  Google Scholar 

  41. Hsu H, Shu HB, Pan MG, Goeddel DV (1996) TRADD-TRAF2 and TRADD-FADD interactions define two distinct TNF receptor 1 signal transduction pathways. Cell 84(2):299–308

    Article  CAS  PubMed  Google Scholar 

  42. Pobezinskaya YL, Kim YS, Choksi S, Morgan MJ, Li T, Liu C, Liu Z (2008) The function of TRADD in signaling through tumor necrosis factor receptor 1 and TRIF-dependent Toll-like receptors. Nat Immunol 9(9):1047–1054. doi:10.1038/ni.1639

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. 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. doi:10.1146/annurev.immunol.25.022106.141656

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Pellegrini M, Bath S, Marsden VS, Huang DC, Metcalf D, Harris AW, Strasser A (2005) FADD and caspase-8 are required for cytokine-induced proliferation of hemopoietic progenitor cells. Blood 106(5):1581–1589. doi:10.1182/blood-2005-01-0284

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Imtiyaz HZ, Zhou X, Zhang H, Chen D, Hu T, Zhang J (2009) The death domain of FADD is essential for embryogenesis, lymphocyte development, and proliferation. J Biol Chem 284(15):9917–9926. doi:10.1074/jbc.M900249200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Krajewska M, You Z, Rong J, Kress C, Huang X, Yang J, Kyoda T, Leyva R, Banares S, Hu Y, Sze CH, Whalen MJ, Salmena L, Hakem R, Head BP, Reed JC, Krajewski S (2011) Neuronal deletion of caspase 8 protects against brain injury in mouse models of controlled cortical impact and kainic acid-induced excitotoxicity. PLoS One 6(9):e24341. doi:10.1371/journal.pone.0024341

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Kang TB, Ben-Moshe T, Varfolomeev EE, Pewzner-Jung Y, Yogev N, Jurewicz A, Waisman A, Brenner O, Haffner R, Gustafsson E, Ramakrishnan P, Lapidot T, Wallach D (2004) Caspase-8 serves both apoptotic and nonapoptotic roles. J Immunol 173(5):2976–2984

    Article  CAS  PubMed  Google Scholar 

  48. Lemmers B, Salmena L, Bidere N, Su H, Matysiak-Zablocki E, Murakami K, Ohashi PS, Jurisicova A, Lenardo M, Hakem R, Hakem A (2007) Essential role for caspase-8 in Toll-like receptors and NFkappaB signaling. J Biol Chem 282(10):7416–7423. doi:10.1074/jbc.M606721200

    Article  CAS  PubMed  Google Scholar 

  49. Beisner DR, Ch’en IL, Kolla RV, Hoffmann A, Hedrick SM (2005) Cutting edge: innate immunity conferred by B cells is regulated by caspase-8. J Immunol 175(6):3469–3473

    Article  CAS  PubMed  Google Scholar 

  50. Salmena L, Hakem R (2005) Caspase-8 deficiency in T cells leads to a lethal lymphoinfiltrative immune disorder. J Exp Med 202(6):727–732. doi:10.1084/jem.20050683

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Kang TB, Yang SH, Toth B, Kovalenko A, Wallach D (2013) Caspase-8 blocks kinase RIPK3-mediated activation of the NLRP3 inflammasome. Immunity 38(1):27–40. doi:10.1016/j.immuni.2012.09.015

    Article  CAS  PubMed  Google Scholar 

  52. Hirschi KK (2012) Hemogenic endothelium during development and beyond. Blood 119(21):4823–4827. doi:10.1182/blood-2011-12-353466

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Newton K, Dugger DL, Wickliffe KE, Kapoor N, de Almagro MC, Vucic D, Komuves L, Ferrando RE, French DM, Webster J, Roose-Girma M, Warming S, Dixit VM (2014) Activity of protein kinase RIPK3 determines whether cells die by necroptosis or apoptosis. Science 343(6177):1357–1360. doi:10.1126/science.1249361

    Article  CAS  PubMed  Google Scholar 

  54. Mandal P, Berger SB, Pillay S, Moriwaki K, Huang C, Guo H, Lich JD, Finger J, Kasparcova V, Votta B, Ouellette M, King BW, Wisnoski D, Lakdawala AS, DeMartino MP, Casillas LN, Haile PA, Sehon CA, Marquis RW, Upton J, Daley-Bauer LP, Roback L, Ramia N, Dovey CM, Carette JE, Chan FK, Bertin J, Gough PJ, Mocarski ES, Kaiser WJ (2014) RIP3 induces apoptosis independent of pronecrotic kinase activity. Mol Cell 56(4):481–495. doi:10.1016/j.molcel.2014.10.021

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Mihaly SR, Ninomiya-Tsuji J, Morioka S (2014) TAK1 control of cell death. Cell Death Differ 21(11):1667–1676. doi:10.1038/cdd.2014.123

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Dondelinger Y, Aguileta MA, Goossens V, Dubuisson C, Grootjans S, Dejardin E, Vandenabeele P, Bertrand MJ (2013) RIPK3 contributes to TNFR1-mediated RIPK1 kinase-dependent apoptosis in conditions of cIAP1/2 depletion or TAK1 kinase inhibition. Cell Death Differ 20(10):1381–1392. doi:10.1038/cdd.2013.94

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Shim JH, Xiao C, Paschal AE, Bailey ST, Rao P, Hayden MS, Lee KY, Bussey C, Steckel M, Tanaka N, Yamada G, Akira S, Matsumoto K, Ghosh S (2005) TAK1, but not TAB 1 or TAB 2, plays an essential role in multiple signaling pathways in vivo. Genes Dev 19(22):2668–2681. doi:10.1101/gad.1360605

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Morioka S, Broglie P, Omori E, Ikeda Y, Takaesu G, Matsumoto K, Ninomiya-Tsuji J (2014) TAK1 kinase switches cell fate from apoptosis to necrosis following TNF stimulation. J Cell Biol 204(4):607–623. doi:10.1083/jcb.201305070

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Peltzer N, Rieser E, Taraborrelli L, Draber P, Darding M, Pernaute B, Shimizu Y, Sarr A, Draberova H, Montinaro A, Martinez-Barbera JP, Silke J, Rodriguez TA, Walczak H (2014) HOIP deficiency causes embryonic lethality by aberrant TNFR1-mediated endothelial cell death. Cell Rep 9(1):153–165. doi:10.1016/j.celrep.2014.08.066

    Article  CAS  PubMed  Google Scholar 

  60. Xiao Y, Li H, Zhang J, Volk A, Zhang S, Wei W, Zhang S, Breslin P, Zhang J (2011) TNF-alpha/Fas-RIP-1-induced cell death signaling separates murine hematopoietic stem cells/progenitors into 2 distinct populations. Blood 118(23):6057–6067. doi:10.1182/blood-2011-06-359448

    Article  CAS  PubMed  Google Scholar 

  61. Chang H, Huylebroeck D, Verschueren K, Guo Q, Matzuk MM, Zwijsen A (1999) Smad5 knockout mice die at mid-gestation due to multiple embryonic and extraembryonic defects. Development 126(8):1631–1642

    CAS  PubMed  Google Scholar 

  62. Beg AA, Baltimore D (1996) An essential role for NF-kappaB in preventing TNF-alpha-induced cell death. Science 274(5288):782–784

    Article  CAS  PubMed  Google Scholar 

  63. Li Q, Van Antwerp D, Mercurio F, Lee KF, Verma IM (1999) Severe liver degeneration in mice lacking the IkappaB kinase 2 gene. Science 284(5412):321–325

    Article  CAS  PubMed  Google Scholar 

  64. Rudolph D, Yeh WC, Wakeham A, Rudolph B, Nallainathan D, Potter J, Elia AJ, Mak TW (2000) Severe liver degeneration and lack of NF-kappaB activation in NEMO/IKKgamma-deficient mice. Genes Dev 14(7):854–862

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Kelliher MA, Grimm S, Ishida Y, Kuo F, Stanger BZ, Leder P (1998) The death domain kinase RIP mediates the TNF-induced NF-kappaB signal. Immunity 8(3):297–303

    Article  CAS  PubMed  Google Scholar 

  66. Silke J, Vucic D (2014) IAP family of cell death and signaling regulators. Methods Enzymol 545:35–65. doi:10.1016/B978-0-12-801430-1.00002-0

    Article  CAS  PubMed  Google Scholar 

  67. Moulin M, Anderton H, Voss AK, Thomas T, Wong WW, Bankovacki A, Feltham R, Chau D, Cook WD, Silke J, Vaux DL (2012) IAPs limit activation of RIP kinases by TNF receptor 1 during development. EMBO J 31(7):1679–1691. doi:10.1038/emboj.2012.18

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. de Almagro MC, Goncharov T, Newton K, Vucic D (2015) Cellular IAP proteins and LUBAC differentially regulate necrosome-associated RIP1 ubiquitination. Cell Death Dis 6:e1800. doi:10.1038/cddis.2015.158

    Article  PubMed  PubMed Central  Google Scholar 

  69. Lee EG, Boone DL, Chai S, Libby SL, Chien M, Lodolce JP, Ma A (2000) Failure to regulate TNF-induced NF-kappaB and cell death responses in A20-deficient mice. Science 289(5488):2350–2354

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Reiley WW, Zhang M, Jin W, Losiewicz M, Donohue KB, Norbury CC, Sun SC (2006) Regulation of T cell development by the deubiquitinating enzyme CYLD. Nat Immunol 7(4):411–417. doi:10.1038/ni1315

    Article  CAS  PubMed  Google Scholar 

  71. Reiley WW, Jin W, Lee AJ, Wright A, Wu X, Tewalt EF, Leonard TO, Norbury CC, Fitzpatrick L, Zhang M, Sun SC (2007) Deubiquitinating enzyme CYLD negatively regulates the ubiquitin-dependent kinase Tak1 and prevents abnormal T cell responses. J Exp Med 204(6):1475–1485. doi:10.1084/jem.20062694

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Sun SC (2008) Deubiquitylation and regulation of the immune response. Nat Rev Immunol 8(7):501–511. doi:10.1038/nri2337

    Article  CAS  PubMed  Google Scholar 

  73. Dharaneeswaran H, Abid MR, Yuan L, Dupuis D, Beeler D, Spokes KC, Janes L, Sciuto T, Kang PM, Jaminet SC, Dvorak A, Grant MA, Regan ER, Aird WC (2014) FOXO1-mediated activation of Akt plays a critical role in vascular homeostasis. Circ Res 115(2):238–251. doi:10.1161/CIRCRESAHA.115.303227

    Article  CAS  PubMed  Google Scholar 

  74. Furuyama T, Kitayama K, Shimoda Y, Ogawa M, Sone K, Yoshida-Araki K, Hisatsune H, Nishikawa S, Nakayama K, Nakayama K, Ikeda K, Motoyama N, Mori N (2004) Abnormal angiogenesis in Foxo1 (Fkhr)-deficient mice. J Biol Chem 279(33):34741–34749. doi:10.1074/jbc.M314214200

    Article  CAS  PubMed  Google Scholar 

  75. Xue Y, Gao X, Lindsell CE, Norton CR, Chang B, Hicks C, Gendron-Maguire M, Rand EB, Weinmaster G, Gridley T (1999) Embryonic lethality and vascular defects in mice lacking the Notch ligand Jagged1. Hum Mol Genet 8(5):723–730

    Article  CAS  PubMed  Google Scholar 

  76. Wu ZQ, Rowe RG, Lim KC, Lin Y, Willis A, Tang Y, Li XY, Nor JE, Maillard I, Weiss SJ (2014) A Snail1/Notch1 signalling axis controls embryonic vascular development. Nat Commun 5:3998. doi:10.1038/ncomms4998

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Oh S, Janknecht R (2012) Histone demethylase JMJD5 is essential for embryonic development. Biochem Biophys Res Commun 420(1):61–65. doi:10.1016/j.bbrc.2012.02.115

    Article  CAS  PubMed  Google Scholar 

  78. Satyanarayana A, Gudmundsson KO, Chen X, Coppola V, Tessarollo L, Keller JR, Hou SX (2010) RapGEF2 is essential for embryonic hematopoiesis but dispensable for adult hematopoiesis. Blood 116(16):2921–2931. doi:10.1182/blood-2010-01-262964

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Grisendi S, Bernardi R, Rossi M, Cheng K, Khandker L, Manova K, Pandolfi PP (2005) Role of nucleophosmin in embryonic development and tumorigenesis. Nature 437(7055):147–153. doi:10.1038/nature03915

    Article  CAS  PubMed  Google Scholar 

  80. Zhang M, Harashima N, Moritani T, Huang W, Harada M (2015) The roles of ROS and caspases in TRAIL-induced apoptosis and necroptosis in human pancreatic cancer cells. PLoS One 10(5):e0127386. doi:10.1371/journal.pone.0127386

    Article  PubMed  PubMed Central  Google Scholar 

  81. Kaiser WJ, Daley-Bauer LP, Thapa RJ, Mandal P, Berger SB, Huang C, Sundararajan A, Guo H, Roback L, Speck SH, Bertin J, Gough PJ, Balachandran S, Mocarski ES (2014) RIP1 suppresses innate immune necrotic as well as apoptotic cell death during mammalian parturition. Proc Natl Acad Sci USA 111(21):7753–7758. doi:10.1073/pnas.1401857111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Rickard JA, O’Donnell JA, Evans JM, Lalaoui N, Poh AR, Rogers T, Vince JE, Lawlor KE, Ninnis RL, Anderton H, Hall C, Spall SK, Phesse TJ, Abud HE, Cengia LH, Corbin J, Mifsud S, Di Rago L, Metcalf D, Ernst M, Dewson G, Roberts AW, Alexander WS, Murphy JM, Ekert PG, Masters SL, Vaux DL, Croker BA, Gerlic M, Silke J (2014) RIPK1 regulates RIPK3-MLKL-driven systemic inflammation and emergency hematopoiesis. Cell 157(5):1175–1188. doi:10.1016/j.cell.2014.04.019

    Article  CAS  PubMed  Google Scholar 

  83. Zhang H, Zhou X, McQuade T, Li J, Chan FK, Zhang J (2011) Functional complementation between FADD and RIP1 in embryos and lymphocytes. Nature 471(7338):373–376. doi:10.1038/nature09878

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Berger SB, Kasparcova V, Hoffman S, Swift B, Dare L, Schaeffer M, Capriotti C, Cook M, Finger J, Hughes-Earle A, Harris PA, Kaiser WJ, Mocarski ES, Bertin J, Gough PJ (2014) Cutting Edge: rIP1 kinase activity is dispensable for normal development but is a key regulator of inflammation in SHARPIN-deficient mice. J Immunol 192(12):5476–5480. doi:10.4049/jimmunol.1400499

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Chan FK, Shisler J, Bixby JG, Felices M, Zheng L, Appel M, Orenstein J, Moss B, Lenardo MJ (2003) A role for tumor necrosis factor receptor-2 and receptor-interacting protein in programmed necrosis and antiviral responses. J Biol Chem 278(51):51613–51621. doi:10.1074/jbc.M305633200

    Article  CAS  PubMed  Google Scholar 

  86. Dannappel M, Vlantis K, Kumari S, Polykratis A, Kim C, Wachsmuth L, Eftychi C, Lin J, Corona T, Hermance N, Zelic M, Kirsch P, Basic M, Bleich A, Kelliher M, Pasparakis M (2014) RIPK1 maintains epithelial homeostasis by inhibiting apoptosis and necroptosis. Nature 513(7516):90–94. doi:10.1038/nature13608

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Gunther C, Martini E, Wittkopf N, Amann K, Weigmann B, Neumann H, Waldner MJ, Hedrick SM, Tenzer S, Neurath MF, Becker C (2011) Caspase-8 regulates TNF-alpha-induced epithelial necroptosis and terminal ileitis. Nature 477(7364):335–339. doi:10.1038/nature10400

    Article  PubMed  PubMed Central  Google Scholar 

  88. Takahashi N, Vereecke L, Bertrand MJ, Duprez L, Berger SB, Divert T, Goncalves A, Sze M, Gilbert B, Kourula S, Goossens V, Lefebvre S, Gunther C, Becker C, Bertin J, Gough PJ, Declercq W, van Loo G, Vandenabeele P (2014) RIPK1 ensures intestinal homeostasis by protecting the epithelium against apoptosis. Nature 513(7516):95–99. doi:10.1038/nature13706

    Article  CAS  PubMed  Google Scholar 

  89. Welz PS, Wullaert A, Vlantis K, Kondylis V, Fernandez-Majada V, Ermolaeva M, Kirsch P, Sterner-Kock A, van Loo G, Pasparakis M (2011) FADD prevents RIP3-mediated epithelial cell necrosis and chronic intestinal inflammation. Nature 477(7364):330–334. doi:10.1038/nature10273

    Article  CAS  PubMed  Google Scholar 

  90. Lee P, Lee DJ, Chan C, Chen SW, Ch’en I, Jamora C (2009) Dynamic expression of epidermal caspase 8 simulates a wound healing response. Nature 458(7237):519–523. doi:10.1038/nature07687

    Article  CAS  PubMed  Google Scholar 

  91. Kovalenko A, Kim JC, Kang TB, Rajput A, Bogdanov K, Dittrich-Breiholz O, Kracht M, Brenner O, Wallach D (2009) Caspase-8 deficiency in epidermal keratinocytes triggers an inflammatory skin disease. J Exp Med 206(10):2161–2177. doi:10.1084/jem.20090616

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Bonnet MC, Preukschat D, Welz PS, van Loo G, Ermolaeva MA, Bloch W, Haase I, Pasparakis M (2011) The adaptor protein FADD protects epidermal keratinocytes from necroptosis in vivo and prevents skin inflammation. Immunity 35(4):572–582. doi:10.1016/j.immuni.2011.08.014

    Article  CAS  PubMed  Google Scholar 

  93. Tanzer MC, Matti I, Hildebrand JM, Young SN, Wardak A, Tripaydonis A, Petrie EJ, Mildenhall AL, Vaux DL, Vince JE, Czabotar PE, Silke J, Murphy JM (2016) Evolutionary divergence of the necroptosis effector MLKL. Cell Death Differ. doi:10.1038/cdd.2015.169

    PubMed  Google Scholar 

  94. Clements WK, Traver D (2013) Signalling pathways that control vertebrate haematopoietic stem cell specification. Nat Rev Immunol 13(5):336–348. doi:10.1038/nri3443

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Eimon PM, Kratz E, Varfolomeev E, Hymowitz SG, Stern H, Zha J, Ashkenazi A (2006) Delineation of the cell-extrinsic apoptosis pathway in the zebrafish. Cell Death Differ 13(10):1619–1630. doi:10.1038/sj.cdd.4402015

    Article  CAS  PubMed  Google Scholar 

  96. Sun L, Wang H, Wang Z, He S, Chen S, Liao D, Wang L, Yan J, Liu W, Lei X, Wang X (2012) Mixed lineage kinase domain-like protein mediates necrosis signaling downstream of RIP3 kinase. Cell 148(1–2):213–227. doi:10.1016/j.cell.2011.11.031

    Article  CAS  PubMed  Google Scholar 

  97. Su H, Bidere N, Zheng L, Cubre A, Sakai K, Dale J, Salmena L, Hakem R, Straus S, Lenardo M (2005) Requirement for caspase-8 in NF-kappaB activation by antigen receptor. Science 307(5714):1465–1468. doi:10.1126/science.1104765

    Article  CAS  PubMed  Google Scholar 

  98. Wang J, Chun HJ, Wong W, Spencer DM, Lenardo MJ (2001) Caspase-10 is an initiator caspase in death receptor signaling. Proc Natl Acad Sci USA 98(24):13884–13888. doi:10.1073/pnas.241358198

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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  1. Department of Immunology, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA

    Christopher P. Dillon, Bart Tummers, Katherine Baran & Douglas R. Green

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  1. Christopher P. Dillon
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  2. Bart Tummers
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Dillon, C.P., Tummers, B., Baran, K. et al. Developmental checkpoints guarded by regulated necrosis. Cell. Mol. Life Sci. 73, 2125–2136 (2016). https://doi.org/10.1007/s00018-016-2188-z

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