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The molecular machinery of regulated cell death

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Tang, Daolin, Kang, Rui, Berghe, Tom Vanden, Vandenabeele, Peter, Kroemer, Guido·2019·Cell Research
DOI 10.1038/s41422-019-0164-5
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Abstract

Cells may die from accidental cell death (ACD) or regulated cell death (RCD). ACD is a biologically uncontrolled process, whereas RCD involves tightly structured signaling cascades and molecularly defined effector mechanisms. A growing number of novel non-apoptotic forms of RCD have been identified and are increasingly being implicated in various human pathologies. Here, we critically review the current state of the art regarding non-apoptotic types of RCD, including necroptosis, pyroptosis, ferroptosis, entotic cell death, netotic cell death, parthanatos, lysosome-dependent cell death, autophagy-dependent cell death, alkaliptosis and oxeiptosis. The in-depth comprehension of each of these lethal subroutines and their intercellular consequences may uncover novel therapeutic targets for the avoidance of pathogenic cell loss.

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  1. Kerr, J. F., Wyllie, A. H. & Currie, A. R. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br. J. Cancer 26, 239–257 (1972). · DOI · Paper page
  2. Hengartner, M. O., Ellis, R. E. & Horvitz, H. R. Caenorhabditis elegans gene ced-9 protects cells from programmed cell death. Nature 356, 494–499 (1992). · DOI · Paper page
  3. Hengartner, M. O. & Horvitz, H. R. C. elegans cell survival gene ced-9 encodes a functional homolog of the mammalian proto-oncogene bcl-2. Cell 76, 665–676 (1994). · DOI · Paper page
  4. Yuan, J. & Horvitz, H. R. The Caenorhabditis elegans cell death gene ced-4 encodes a novel protein and is expressed during the period of extensive programmed cell death. Development 116, 309–320 (1992). · DOI · Paper page
  5. Schulze-Osthoff, K., Ferrari, D., Los, M., Wesselborg, S. & Peter, M. E. Apoptosis signaling by death receptors. Eur. J. Biochem. 254, 439–459 (1998). · DOI · Paper page
  6. Bredesen, D. E., Mehlen, P. & Rabizadeh, S. Apoptosis and dependence receptors: a molecular basis for cellular addiction. Physiol. Rev. 84, 411–430 (2004). · DOI
  7. McIlwain, D. R., Berger, T. & Mak, T. W. Caspase functions in cell death and disease. Cold Spring Harb. Perspect. Biol. https://doi.org/10.1101/cshperspect.a026716 (2015). · DOI · Paper page
  8. Galluzzi, L., Lopez-Soto, A., Kumar, S. & Kroemer, G. Caspases connect cell-death signaling to organismal homeostasis. Immunity 44, 221–231 (2016). · DOI · Paper page
  9. Schweichel, J. U. & Merker, H. J. The morphology of various types of cell death in prenatal tissues. Teratology 7, 253–266 (1973). · DOI · Paper page
  10. Kerr, J. F. Shrinkage necrosis: a distinct mode of cellular death. J. Pathol. 105, 13–20 (1971). · DOI · Paper page
  11. Nassour, J. et al. Autophagic cell death restricts chromosomal instability during replicative crisis. Nature https://doi.org/10.1038/s41586-019-0885-0 (2019). · DOI · Paper page
  12. Weinlich, R., Oberst, A., Beere, H. M. & Green, D. R. Necroptosis in development, inflammation and disease. Nat. Rev. Mol. Cell Biol. 18, 127–136 (2017). · DOI · Paper page
  13. Galluzzi, L. et al. Essential versus accessory aspects of cell death: recommendations of the NCCD 2015. Cell Death Differ. 22, 58–73 (2015). · DOI · Paper page
  14. Ray, C. A. & Pickup, D. J. The mode of death of pig kidney cells infected with cowpox virus is governed by the expression of the crmA gene. Virology 217, 384–391 (1996). · DOI
  15. Laster, S. M., Wood, J. G. & Gooding, L. R. Tumor necrosis factor can induce both apoptic and necrotic forms of cell lysis. J. Immunol. 141, 2629–2634 (1988). · DOI · Paper page
  16. Holler, N. et al. Fas triggers an alternative, caspase-8-independent cell death pathway using the kinase RIP as effector molecule. Nat. Immunol. 1, 489–495 (2000). · DOI · Paper page
  17. He, S., Liang, Y., Shao, F. & Wang, X. Toll-like receptors activate programmed necrosis in macrophages through a receptor-interacting kinase-3-mediated pathway. Proc. Natl Acad. Sci. USA 108, 20054–20059 (2011). · DOI · Paper page
  18. Schock, S. N. et al. Induction of necroptotic cell death by viral activation of the RIG-I or STING pathway. Cell Death Differ. 24, 615–625 (2017). · DOI
  19. Brault, M., Olsen, T. M., Martinez, J., Stetson, D. B. & Oberst, A. Intracellular nucleic acid sensing triggers necroptosis through synergistic type I IFN and TNF signaling. J. Immunol. 200, 2748–2756 (2018). · DOI
  20. Chen, D. et al. PUMA amplifies necroptosis signaling by activating cytosolic DNA sensors. Proc. Natl Acad. Sci. USA 115, 3930–3935 (2018). · DOI
  21. Wang, X., He, Z., Liu, H., Yousefi, S. & Simon, H. U. Neutrophil necroptosis is triggered by ligation of adhesion molecules following GM-CSF priming. J. Immunol. 197, 4090–4100 (2016). · DOI
  22. Vercammen, D. et al. Inhibition of caspases increases the sensitivity of L929 cells to necrosis mediated by tumor necrosis factor. J. Exp. Med. 187, 1477–1485 (1998). · DOI · Paper page
  23. Sun, L. et al. Mixed lineage kinase domain-like protein mediates necrosis signaling downstream of RIP3 kinase. Cell 148, 213–227 (2012). · DOI · Paper page
  24. Zhao, 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. USA 109, 5322–5327 (2012). · DOI · Paper page
  25. Mompean, M. et al. The structure of the necrosome RIPK1-RIPK3 core, a human hetero-amyloid signaling complex. Cell 173, 1244–1253 e1210 (2018). · DOI · Paper page
  26. Xie, Y. et al. Inhibition of aurora kinase A induces necroptosis in pancreatic carcinoma. Gastroenterology 153, 1429–1443 e1425 (2017). · DOI · Paper page
  27. Onizawa, M. et al. The ubiquitin-modifying enzyme A20 restricts ubiquitination of the kinase RIPK3 and protects cells from necroptosis. Nat. Immunol. 16, 618–627 (2015). · DOI · Paper page
  28. Huang, Z. et al. RIP1/RIP3 binding to HSV-1 ICP6 initiates necroptosis to restrict virus propagation in mice. Cell Host. Microbe. 17, 229–242 (2015). · DOI · Paper page
  29. Thapa, R. J. et al. Interferon-induced RIP1/RIP3-mediated necrosis requires PKR and is licensed by FADD and caspases. Proc. Natl Acad. Sci. USA 110, E3109–E3118 (2013). · DOI · Paper page
  30. Robinson, N. et al. Type I interferon induces necroptosis in macrophages during infection with Salmonella enterica serovar Typhimurium. Nat. Immunol. 13, 954–962 (2012). · DOI · Paper page
  31. Wang, H. et al. Mixed lineage kinase domain-like protein MLKL causes necrotic membrane disruption upon phosphorylation by RIP3. Mol. Cell 54, 133–146 (2014). · DOI · Paper page
  32. Dondelinger, Y. et al. MLKL compromises plasma membrane integrity by binding to phosphatidylinositol phosphates. Cell Rep 7, 971–981 (2014). · DOI · Paper page
  33. Chen, X. et al. Translocation of mixed lineage kinase domain-like protein to plasma membrane leads to necrotic cell death. Cell Res. 24, 105–121 (2014). · DOI · Paper page
  34. Li, D. et al. Natural product kongensin A is a non-canonical HSP90 inhibitor that blocks RIP3-dependent necroptosis. Cell Chem Biol 23, 257–266 (2016). · DOI
  35. Jacobsen, A. V. et al. HSP90 activity is required for MLKL oligomerisation and membrane translocation and the induction of necroptotic cell death. Cell Death Dis. 7, e2051 (2016). · DOI · Paper page
  36. Bigenzahn, J. W. et al. An inducible retroviral expression system for tandem affinity purification mass-spectrometry-based proteomics identifies mixed lineage kinase domain-like protein (MLKL) as an heat shock protein 90 (HSP90) client. Mol. Cell. Proteomics. 15, 1139–1150 (2016). · DOI
  37. Gong, Y. N. et al. ESCRT-III acts downstream of MLKL to regulate necroptotic cell death and its consequences. Cell 169, 286–300 e216 (2017). · DOI · Paper page
  38. Yoon, S., Kovalenko, A., Bogdanov, K. & Wallach, D. MLKL, the protein that mediates necroptosis, also regulates endosomal trafficking and extracellular vesicle generation. Immunity 47, 51–65 e57 (2017). · DOI · Paper page
  39. Vanden Berghe, T. et al. Necroptosis, necrosis and secondary necrosis converge on similar cellular disintegration features. Cell Death Differ. 17, 922–930 (2010). · DOI · Paper page
  40. 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 148, 228–243 (2012). · DOI · Paper page
  41. Zhang, Y. et al. RIP1 autophosphorylation is promoted by mitochondrial ROS and is essential for RIP3 recruitment into necrosome. Nat. Commun. 8, 14329 (2017). · DOI · Paper page
  42. Yang, Z. et al. RIP3 targets pyruvate dehydrogenase complex to increase aerobic respiration in TNF-induced necroptosis. Nat. Cell Biol. 20, 186–197 (2018). · DOI · Paper page
  43. Remijsen, Q. et al. Depletion of RIPK3 or MLKL blocks TNF-driven necroptosis and switches towards a delayed RIPK1 kinase-dependent apoptosis. Cell Death Dis. 5, e1004 (2014). · DOI · Paper page
  44. Yoon, S., Bogdanov, K., Kovalenko, A. & Wallach, D. Necroptosis is preceded by nuclear translocation of the signaling proteins that induce it. Cell Death Differ. 23, 253–260 (2016). · DOI
  45. Weber, K., Roelandt, R., Bruggeman, I., Estornes, Y. & Vandenabeele, P. Nuclear RIPK3 and MLKL contribute to cytosolic necrosome formation and necroptosis. Commun Biol 1, 6 (2018). · DOI · Paper page
  46. Wang, X., Yousefi, S. & Simon, H. U. Necroptosis and neutrophil-associated disorders. Cell Death Dis. 9, 111 (2018). · DOI
  47. Newton, K. et al. Activity of protein kinase RIPK3 determines whether cells die by necroptosis or apoptosis. Science 343, 1357–1360 (2014). · DOI · Paper page
  48. Lawlor, K. E. et al. RIPK3 promotes cell death and NLRP3 inflammasome activation in the absence of MLKL. Nat. Commun. 6, 6282 (2015). · DOI · Paper page
  49. Shan, B., Pan, H., Najafov, A. & Yuan, J. Necroptosis in development and diseases. Genes Dev. 32, 327–340 (2018). · DOI · Paper page
  50. Dillon, C. P., Tummers, B., Baran, K. & Green, D. R. Developmental checkpoints guarded by regulated necrosis. Cell. Mol. Life Sci. 73, 2125–2136 (2016). · DOI
  51. Galluzzi, L., Kepp, O., Chan, F. K. & Kroemer, G. Necroptosis: mechanisms and relevance to disease. Annu. Rev. Pathol. 12, 103–130 (2017). · DOI · Paper page
  52. Vanden Berghe, T. et al. Passenger mutations confound interpretation of all genetically modified congenic mice. Immunity 43, 200–209 (2015). · DOI · Paper page
  53. Fink, S. L. & Cookson, B. T. Apoptosis, pyroptosis, and necrosis: mechanistic description of dead and dying eukaryotic cells. Infect. Immun. 73, 1907–1916 (2005). · DOI · Paper page
  54. Brennan, M. A. & Cookson, B. T. Salmonella induces macrophage death by caspase-1-dependent necrosis. Mol. Microbiol. 38, 31–40 (2000). · DOI · Paper page
  55. Hersh, D. et al. The Salmonella invasin SipB induces macrophage apoptosis by binding to caspase-1. Proc. Natl Acad. Sci. USA 96, 2396–2401 (1999). · DOI · Paper page
  56. Broz, P. & Dixit, V. M. Inflammasomes: mechanism of assembly, regulation and signalling. Nat. Rev. Immunol. 16, 407–420 (2016). · DOI · Paper page
  57. Chen, X. et al. Pyroptosis is driven by non-selective gasdermin-D pore and its morphology is different from MLKL channel-mediated necroptosis. Cell Res. 26, 1007–1020 (2016). · DOI · Paper page
  58. Rathkey, J. K. et al. Chemical disruption of the pyroptotic pore-forming protein gasdermin D inhibits inflammatory cell death and sepsis. Sci. Immunol. https://doi.org/10.1126/sciimmunol.aat2738 (2018). · DOI · Paper page
  59. Hagar, J. A., Powell, D. A., Aachoui, Y., Ernst, R. K. & Miao, E. A. Cytoplasmic LPS activates caspase-11: implications in TLR4-independent endotoxic shock. Science 341, 1250–1253 (2013). · DOI · Paper page
  60. Kayagaki, N. et al. Noncanonical inflammasome activation by intracellular LPS independent of TLR4. Science 341, 1246–1249 (2013). · DOI · Paper page
  61. Vanaja, S. K. et al. Bacterial outer membrane vesicles mediate cytosolic localization of LPS and caspase-11 activation. Cell 165, 1106–1119 (2016). · DOI · Paper page
  62. Deng, M. et al. The endotoxin delivery protein HMGB1 mediates caspase-11-dependent lethality in sepsis. Immunity 49, 740–753 e747 (2018). · DOI · Paper page
  63. Rathinam, V. A. et al. TRIF licenses caspase-11-dependent NLRP3 inflammasome activation by gram-negative bacteria. Cell 150, 606–619 (2012). · DOI · Paper page
  64. Lu, B. et al. Novel role of PKR in inflammasome activation and HMGB1 release. Nature 488, 670–674 (2012). · DOI · Paper page
  65. Xie, M. et al. PKM2-dependent glycolysis promotes NLRP3 and AIM2 inflammasome activation. Nat. Commun. 7, 13280 (2016). · DOI · Paper page
  66. Yang, L. et al. PKM2 regulates the Warburg effect and promotes HMGB1 release in sepsis. Nat. Commun. 5, 4436 (2014). · DOI · Paper page
  67. Moon, J. S. et al. mTORC1-Induced HK1-dependent glycolysis regulates NLRP3 inflammasome activation. Cell Rep 12, 102–115 (2015). · DOI · Paper page
  68. Shi, J. et al. Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death. Nature 526, 660–665 (2015). · DOI · Paper page
  69. He, W. T. et al. Gasdermin D is an executor of pyroptosis and required for interleukin-1beta secretion. Cell Res. 25, 1285–1298 (2015). · DOI · Paper page
  70. Lee, B. L. et al. Caspase-11 auto-proteolysis is crucial for noncanonical inflammasome activation. J. Exp. Med. 215, 2279–2288 (2018). · DOI · Paper page
  71. Kang, R. et al. Lipid peroxidation drives gasdermin D-mediated pyroptosis in lethal polymicrobial sepsis. Cell Host. Microbe. 24, 97–108 e104 (2018). · DOI · Paper page
  72. Ruhl, S. et al. ESCRT-dependent membrane repair negatively regulates pyroptosis downstream of GSDMD activation. Science 362, 956–960 (2018). · DOI · Paper page
  73. Orning, P. et al. Pathogen blockade of TAK1 triggers caspase-8-dependent cleavage of gasdermin D and cell death. Science 362, 1064–1069 (2018). · DOI · Paper page
  74. Sarhan, J. et al. Caspase-8 induces cleavage of gasdermin D to elicit pyroptosis during Yersinia infection. Proc. Natl Acad. Sci. USA 115, E10888–E10897 (2018). · DOI · Paper page
  75. Kambara, H. et al. Gasdermin D exerts anti-inflammatory effects by promoting neutrophil death. Cell Rep 22, 2924–2936 (2018). · DOI · Paper page
  76. Sollberger, G. et al. Gasdermin D plays a vital role in the generation of neutrophil extracellular traps. Sci. Immunol. https://doi.org/10.1126/sciimmunol.aar6689 (2018). · DOI · Paper page
  77. Chen, K. W. et al. Noncanonical inflammasome signaling elicits gasdermin D-dependent neutrophil extracellular traps. Sci. Immunol. https://doi.org/10.1126/sciimmunol.aar6676 (2018). · DOI · Paper page
  78. de Vasconcelos, N. M., Van Opdenbosch, N., Van Gorp, H., Parthoens, E. & Lamkanfi, M. Single-cell analysis of pyroptosis dynamics reveals conserved GSDMD-mediated subcellular events that precede plasma membrane rupture. Cell Death Differ. https://doi.org/10.1038/s41418-018-0106-7 (2018). · DOI · Paper page
  79. Dixon, S. J. et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 149, 1060–1072 (2012). · DOI · Paper page
  80. Neitemeier, S. et al. BID links ferroptosis to mitochondrial cell death pathways. Redox Biol. 12, 558–570 (2017). · DOI · Paper page
  81. Hong, S. H. et al. Molecular crosstalk between ferroptosis and apoptosis: emerging role of ER stress-induced p53-independent PUMA expression. Oncotarget 8, 115164–115178 (2017). · DOI · Paper page
  82. Feng, H. & Stockwell, B. R. Unsolved mysteries: how does lipid peroxidation cause ferroptosis? PLoS Biol. 16, e2006203 (2018). · DOI · Paper page
  83. Hayano, M., Yang, W. S., Corn, C. K., Pagano, N. C. & Stockwell, B. R. Loss of cysteinyl-tRNA synthetase (CARS) induces the transsulfuration pathway and inhibits ferroptosis induced by cystine deprivation. Cell Death Differ. 23, 270–278 (2016). · DOI · Paper page
  84. Woo, J. H. et al. Elucidating compound mechanism of action by network perturbation analysis. Cell 162, 441–451 (2015). · DOI · Paper page
  85. Weiwer, M. et al. Development of small-molecule probes that selectively kill cells induced to express mutant RAS. Bioorg. Med. Chem. Lett. 22, 1822–1826 (2012). · DOI · Paper page
  86. Cao, J. Y. & Dixon, S. J. Mechanisms of ferroptosis. Cell. Mol. Life Sci. 73, 2195–2209 (2016). · DOI · Paper page
  87. Gaschler, M. M. et al. FINO2 initiates ferroptosis through GPX4 inactivation and iron oxidation. Nat. Chem. Biol. 14, 507–515 (2018). · DOI · Paper page
  88. Hassannia, B. et al. Nano-targeted induction of dual ferroptotic mechanisms eradicates high-risk neuroblastoma. J. Clin. Invest. 128, 3341–3355 (2018). · DOI · Paper page
  89. Li, Q. et al. Inhibition of neuronal ferroptosis protects hemorrhagic brain. JCI Insight 2, e90777 (2017). · DOI · Paper page
  90. Yuan, H., Li, X., Zhang, X., Kang, R. & Tang, D. CISD1 inhibits ferroptosis by protection against mitochondrial lipid peroxidation. Biochem. Biophys. Res. Commun. 478, 838–844 (2016). · DOI · Paper page
  91. Ran, Q. et al. Embryonic fibroblasts from Gpx4+/- mice: a novel model for studying the role of membrane peroxidation in biological processes. Free Radic. Biol. Med. 35, 1101–1109 (2003). · DOI
  92. Kagan, V. E. et al. Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis. Nat. Chem. Biol. 13, 81–90 (2017). · DOI · Paper page
  93. Wenzel, S. E. et al. PEBP1 wardens ferroptosis by enabling lipoxygenase generation of lipid death signals. Cell 171, 628–641 e626 (2017). · DOI · Paper page
  94. Sun, X. et al. HSPB1 as a novel regulator of ferroptotic cancer cell death. Oncogene 34, 5617–5625 (2015). · DOI · Paper page
  95. Zhu, S. et al. HSPA5 regulates ferroptotic cell death in cancer cells. Cancer Res. 77, 2064–2077 (2017). · DOI · Paper page
  96. Sun, X. et al. Metallothionein-1G facilitates sorafenib resistance through inhibition of ferroptosis. Hepatology 64, 488–500 (2016). · DOI · Paper page
  97. Chen, D. et al. NRF2 is a major target of ARF in p53-independent tumor suppression. Mol. Cell 68, 224–232 e224 (2017). · DOI · Paper page
  98. Chang, L. C. et al. Heme oxygenase-1 mediates BAY 11-7085 induced ferroptosis. Cancer Lett. 416, 124–137 (2018). · DOI · Paper page
  99. Zhang, Y. et al. BAP1 links metabolic regulation of ferroptosis to tumour suppression. Nat. Cell Biol. https://doi.org/10.1038/s41556-018-0178-0 (2018). · DOI · Paper page
  100. Xie, Y. et al. The tumor suppressor p53 limits ferroptosis by blocking DPP4 activity. Cell Rep 20, 1692–1704 (2017). · DOI · Paper page
  101. Tarangelo, A. et al. p53 suppresses metabolic stress-induced ferroptosis in cancer cells. Cell Rep 22, 569–575 (2018). · DOI · Paper page
  102. Kang, R., Kroemer, G. & Tang, D. The tumor suppressor protein p53 and the ferroptosis network. Free Radic. Biol. Med. https://doi.org/10.1016/j.freeradbiomed.2018.05.074 (2018). · DOI · Paper page
  103. Jennis, M. et al. An African-specific polymorphism in the TP53 gene impairs p53 tumor suppressor function in a mouse model. Genes Dev. 30, 918–930 (2016). · DOI · Paper page
  104. Wu, Z. et al. Chaperone-mediated autophagy is involved in the execution of ferroptosis. Proc. Natl Acad. Sci. USA 116, 2996–3005 (2019). · DOI · Paper page
  105. Gao, M. et al. Ferroptosis is an autophagic cell death process. Cell Res. 26, 1021–1032 (2016). · DOI · Paper page
  106. Song, X. et al. AMPK-mediated BECN1 phosphorylation promotes ferroptosis by directly blocking system Xc(-) activity. Curr. Biol. 28, 2388–2399 e2385 (2018). · DOI · Paper page
  107. Zhou, B. et al. Ferroptosis is a type of autophagy-dependent cell death. Sem. Cancer Biol. pii: S1044-579X(19)30006-9. https://doi.org/10.1016/j.semcancer.2019.03.002 (2019). · DOI · Paper page
  108. Bai, Y. et al. Lipid storage and lipophagy regulates ferroptosis. Biochem. Biophys. Res. Commun. 508, 997–1003 (2019). · DOI · Paper page
  109. Kang, R. & Tang, D. Autophagy and ferroptosis - what’s the connection? Curr Pathobiol Rep 5, 153–159 (2017). · DOI
  110. Tan, S., Schubert, D. & Maher, P. Oxytosis: a novel form of programmed cell death. Curr. Top. Med. Chem. 1, 497–506 (2001). · DOI · Paper page
  111. Murphy, T. H., Malouf, A. T., Sastre, A., Schnaar, R. L. & Coyle, J. T. Calcium-dependent glutamate cytotoxicity in a neuronal cell line. Brain Res. 444, 325–332 (1988). · DOI
  112. Lewerenz, J., Ates, G., Methner, A., Conrad, M. & Maher, P. Oxytosis/ferroptosis-(Re-) emerging roles for oxidative stress-dependent non-apoptotic cell death in diseases of the central nervous system. Front. Neurosci. 12, 214 (2018). · DOI · Paper page
  113. Delettre, C. et al. AIFsh, a novel apoptosis-inducing factor (AIF) pro-apoptotic isoform with potential pathological relevance in human cancer. J. Biol. Chem. 281, 6413–6427 (2006). · DOI
  114. Wang, H. et al. Apoptosis-inducing factor substitutes for caspase executioners in NMDA-triggered excitotoxic neuronal death. J. Neurosci. 24, 10963–10973 (2004). · DOI · Paper page
  115. Nicholson, D. W. et al. Identification and inhibition of the ICE/CED-3 protease necessary for mammalian apoptosis. Nature 376, 37–43 (1995). · DOI · Paper page
  116. Tewari, M. et al. Yama/CPP32 beta, a mammalian homolog of CED-3, is a CrmA-inhibitable protease that cleaves the death substrate poly(ADP-ribose) polymerase. Cell 81, 801–809 (1995). · DOI · Paper page
  117. Wang, R. et al. OGG1-initiated base excision repair exacerbates oxidative stress-induced parthanatos. Cell Death Dis. 9, 628 (2018). · DOI
  118. Andrabi, S. A., Dawson, T. M. & Dawson, V. L. Mitochondrial and nuclear cross talk in cell death: parthanatos. Ann. N. Y. Acad. Sci. 1147, 233–241 (2008). · DOI · Paper page
  119. Wang, Y. et al. Poly(ADP-ribose) (PAR) binding to apoptosis-inducing factor is critical for PAR polymerase-1-dependent cell death (parthanatos). Sci. Signal. 4, ra20 (2011).
  120. Mashimo, M., Kato, J. & Moss, J. ADP-ribosyl-acceptor hydrolase 3 regulates poly (ADP-ribose) degradation and cell death during oxidative stress. Proc. Natl Acad. Sci. USA 110, 18964–18969 (2013). · DOI · Paper page
  121. Wang, Y. et al. A nuclease that mediates cell death induced by DNA damage and poly(ADP-ribose) polymerase-1. Science https://doi.org/10.1126/science.aad6872 (2016). · DOI · Paper page
  122. Jang, K. H. et al. AIF-independent parthanatos in the pathogenesis of dry age-related macular degeneration. Cell Death Dis. 8, e2526 (2017). · DOI
  123. Rodriguez-Vargas, J. M. et al. ROS-induced DNA damage and PARP-1 are required for optimal induction of starvation-induced autophagy. Cell Res. 22, 1181–1198 (2012). · DOI · Paper page
  124. Xu, X. et al. The role of PARP activation in glutamate-induced necroptosis in HT-22 cells. Brain Res. 1343, 206–212 (2010). · DOI
  125. Brouwer, M., de Ley, L., Feltkamp, C. A., Elema, J. & Jongsma, A. P. Serum-dependent “cannibalism” and autodestruction in cultures of human small cell carcinoma of the lung. Cancer Res. 44, 2947–2951 (1984).
  126. Durgan, J. & Florey, O. Cancer cell cannibalism: multiple triggers emerge for entosis. Biochim. Biophys. Acta Mol. Cell Res. 1865, 831–841 (2018). · DOI
  127. Martins, I. et al. Entosis: the emerging face of non-cell-autonomous type IV programmed death. Biomed J 40, 133–140 (2017). · DOI
  128. Sun, Q., Cibas, E. S., Huang, H., Hodgson, L. & Overholtzer, M. Induction of entosis by epithelial cadherin expression. Cell Res. 24, 1288–1298 (2014). · DOI · Paper page
  129. Sottile, F., Aulicino, F., Theka, I. & Cosma, M. P. Mesenchymal stem cells generate distinct functional hybrids in vitro via cell fusion or entosis. Sci. Rep. 6, 36863 (2016). · DOI
  130. Wen, S., Shang, Z., Zhu, S., Chang, C. & Niu, Y. Androgen receptor enhances entosis, a non-apoptotic cell death, through modulation of Rho/ROCK pathway in prostate cancer cells. Prostate 73, 1306–1315 (2013). · DOI · Paper page
  131. Wan, Q. et al. Regulation of myosin activation during cell-cell contact formation by Par3-Lgl antagonism: entosis without matrix detachment. Mol. Biol. Cell. 23, 2076–2091 (2012). · DOI · Paper page
  132. Xia, P. et al. Aurora A orchestrates entosis by regulating a dynamic MCAK-TIP150 interaction. J. Mol. Cell Biol. 6, 240–254 (2014). · DOI
  133. Heckmann, B. L., Boada-Romero, E., Cunha, L. D., Magne, J. & Green, D. R. LC3-associated phagocytosis and inflammation. J. Mol. Biol. 429, 3561–3576 (2017). · DOI · Paper page
  134. Arazna, M., Pruchniak, M. P. & Demkow, U. Reactive Oxygen Species, Granulocytes, and NETosis. Adv. Exp. Med. Biol. 836, 1–7 (2015).
  135. Kazzaz, N. M., Sule, G. & Knight, J. S. Intercellular interactions as regulators of NETosis. Front. Immunol. 7, 453 (2016). · DOI
  136. Remijsen, Q. et al. Dying for a cause: NETosis, mechanisms behind an antimicrobial cell death modality. Cell Death Differ. 18, 581–588 (2011). · DOI · Paper page
  137. Branzk, N. & Papayannopoulos, V. Molecular mechanisms regulating NETosis in infection and disease. Semin. Immunopathol. 35, 513–530 (2013). · DOI · Paper page
  138. Skendros, P., Mitroulis, I. & Ritis, K. Autophagy in neutrophils: from granulopoiesis to neutrophil extracellular traps. Front. Cell. Dev. Biol. 6, 109 (2018). · DOI
  139. Hemmers, S., Teijaro, J. R., Arandjelovic, S. & Mowen, K. A. PAD4-mediated neutrophil extracellular trap formation is not required for immunity against influenza infection. PLoS ONE 6, e22043 (2011). · DOI · Paper page
  140. Mitroulis, I. et al. Neutrophil extracellular trap formation is associated with IL-1beta and autophagy-related signaling in gout. PLoS ONE 6, e29318 (2011). · DOI · Paper page
  141. Neubert, E. et al. Chromatin swelling drives neutrophil extracellular trap release. Nat. Commun. 9, 3767 (2018). · DOI · Paper page
  142. Okubo, K. et al. Lactoferrin suppresses neutrophil extracellular traps release in inflammation. EBioMedicine 10, 204–215 (2016). · DOI · Paper page
  143. Aits, S. & Jaattela, M. Lysosomal cell death at a glance. J. Cell. Sci. 126, 1905–1912 (2013). · DOI · Paper page
  144. Franko, J., Pomfy, M. & Prosbova, T. Apoptosis and cell death (mechanisms, pharmacology and promise for the future). Acta Medica (Hradec. Kralove) 43, 63–68 (2000). · doi:10.14712/18059694.2019.115
  145. Kroemer, G. & Jaattela, M. Lysosomes and autophagy in cell death control. Nat. Rev. Cancer 5, 886–897 (2005). · DOI · Paper page
  146. Gao, H. et al. Ferroptosis is a lysosomal cell death process. Biochem. Biophys. Res. Commun. 503, 1550–1556 (2018). · DOI · Paper page
  147. Repnik, U., Stoka, V., Turk, V. & Turk, B. Lysosomes and lysosomal cathepsins in cell death. Biochim. Biophys. Acta 1824, 22–33 (2012). · DOI · Paper page
  148. Wu, G. S., Saftig, P., Peters, C. & El-Deiry, W. S. Potential role for cathepsin D in p53-dependent tumor suppression and chemosensitivity. Oncogene 16, 2177–2183 (1998). · DOI · Paper page
  149. Liu, N. et al. NF-kappaB protects from the lysosomal pathway of cell death. EMBO J. 22, 5313–5322 (2003). · DOI
  150. Colletti, G. A. et al. Loss of lysosomal ion channel transient receptor potential channel mucolipin-1 (TRPML1) leads to cathepsin B-dependent apoptosis. J. Biol. Chem. 287, 8082–8091 (2012). · DOI
  151. Terman, A. & Kurz, T. Lysosomal iron, iron chelation, and cell death. Antioxid. Redox. Signal. 18, 888–898 (2013). · DOI · Paper page
  152. Platt, F. M., Boland, B. & van der Spoel, A. C. The cell biology of disease: lysosomal storage disorders: the cellular impact of lysosomal dysfunction. J. Cell. Biol. 199, 723–734 (2012). · DOI · Paper page
  153. Klionsky, D. J. Autophagy: from phenomenology to molecular understanding in less than a decade. Nat. Rev. Mol. Cell Biol. 8, 931–937 (2007). · DOI · Paper page
  154. Liu, Y. & Levine, B. Autosis and autophagic cell death: the dark side of autophagy. Cell Death Differ. 22, 367–376 (2015). · DOI · Paper page
  155. Denton, D. & Kumar, S. Autophagy-dependent cell death. Cell Death Differ. https://doi.org/10.1038/s41418-018-0252-y (2018). · DOI · Paper page
  156. Kriel, J. & Loos, B. The good, the bad and the autophagosome: exploring unanswered questions of autophagy-dependent cell death. Cell Death Differ. https://doi.org/10.1038/s41418-018-0267-4 (2019). · DOI
  157. Sousa, L. et al. Effects of iron overload on the activity of Na,K-ATPase and lipid profile of the human erythrocyte membrane. PLoS ONE 10, e0132852 (2015). · DOI
  158. Song, X. et al. JTC801 induces pH-dependent death specifically in cancer cells and slows growth of tumors in mice. Gastroenterology 154, 1480–1493 (2018). · DOI · Paper page
  159. Zheng, C. J., Yang, L. L., Liu, J. & Zhong, L. JTC-801 exerts anti-proliferative effects in human osteosarcoma cells by inducing apoptosis. J. Recept. Signal. Transduct. Res. 38, 133–140 (2018). · DOI
  160. Pochet, J. M., Laterre, P. F., Jadoul, M. & Devuyst, O. Metabolic alkalosis in the intensive care unit. Acta Clin. Belg. 56, 2–9 (2001). · doi:10.1179/acb.2001.002
  161. Holze, C. et al. Oxeiptosis, a ROS-induced caspase-independent apoptosis-like cell-death pathway. Nat. Immunol. 19, 130–140 (2018). · DOI · Paper page
  162. Saito, Y. et al. Turning point in apoptosis/necrosis induced by hydrogen peroxide. Free. Radic. Res. 40, 619–630 (2006). · DOI · Paper page
  163. Ingold, I. et al. Selenium Utilization by GPX4 is required to prevent hydroperoxide-induced ferroptosis. Cell 172, 409–422 e421 (2018). · DOI · Paper page
  164. Galluzzi, L., Buque, A., Kepp, O., Zitvogel, L. & Kroemer, G. Immunogenic cell death in cancer and infectious disease. Nat. Rev. Immunol. 17, 97–111 (2017). · DOI · Paper page
  165. Tang, D., Kang, R., Coyne, C. B., Zeh, H. J. & Lotze, M. T. PAMPs and DAMPs: signal 0s that spur autophagy and immunity. Immunol. Rev. 249, 158–175 (2012). · DOI · Paper page
  166. Hou, W. et al. Strange attractors: DAMPs and autophagy link tumor cell death and immunity. Cell Death Dis. 4, e966 (2013). · DOI · Paper page
  167. Yatim, N. et al. RIPK1 and NF-kappaB signaling in dying cells determines cross-priming of CD8(+) T cells. Science 350, 328–334 (2015). · DOI · Paper page
  168. Ahn, J., Xia, T., Rabasa Capote, A., Betancourt, D. & Barber, G. N. Extrinsic Phagocyte-dependent STING signaling dictates the immunogenicity of dying cells. Cancer Cell. 33, 862–873 e865 (2018). · DOI · Paper page
  169. Ma, Y. et al. Contribution of IL-17-producing gamma delta T cells to the efficacy of anticancer chemotherapy. J. Exp. Med. 208, 491–503 (2011). · DOI · Paper page
  170. Ren, J. et al. The RIP3-RIP1-NF-kappaB signaling axis is dispensable for necroptotic cells to elicit cross-priming of CD8(+) T cells. Cell. Mol. Immunol. 14, 639–642 (2017). · doi:10.1038/cmi.2017.31
  171. Michaud, M. et al. Autophagy-dependent anticancer immune responses induced by chemotherapeutic agents in mice. Science 334, 1573–1577 (2011). · DOI · Paper page
  172. Yang, M. et al. TFAM is a novel mediator of immunogenic cancer cell death. Oncoimmunology 7, e1431086 (2018). · DOI
  173. Kang, R. et al. HMGB1 in health and disease. Mol. Aspects. Med. 40, 1–116 (2014). · DOI · Paper page
  174. Li, C. et al. PINK1 and PARK2 suppress pancreatic tumorigenesis through control of mitochondrial iron-mediated immunometabolism. Dev. Cell. 46, 441–455 e448 (2018). · DOI · Paper page
  175. Ito, T. et al. Proteolytic cleavage of high mobility group Box 1 protein by thrombin-thrombomodulin complexes. Arterioscler. Thromb. Vasc. Biol. 28, 1825–1830 (2008). · DOI · Paper page
  176. Yu, H. et al. Role of high-mobility group Box 1 protein and poly(ADP-ribose) polymerase 1 degradation in Chlamydia trachomatis-induced cytopathicity. Infect. Immun. 78, 3288–3297 (2010). · DOI
  177. Yu, Y., Tang, D. & Kang, R. Oxidative stress-mediated HMGB1 biology. Front. Physiol. 6, 93 (2015). · DOI · Paper page
  178. Fujiki, K., Inamura, H., Sugaya, T. & Matsuoka, M. Blockade of ALK4/5 signaling suppresses cadmium- and erastin-induced cell death in renal proximal tubular epithelial cells via distinct signaling mechanisms. Cell Death Differ. https://doi.org/10.1038/s41418-019-0307-8 (2019). · DOI
  179. Song, X. et al. FANCD2 protects against bone marrow injury from ferroptosis. Biochem. Biophys. Res. Commun. 480, 443–449 (2016). · DOI · Paper page
  180. Brown, C. W., Amante, J. J., Goel, H. L. & Mercurio, A. M. The alpha6beta4 integrin promotes resistance to ferroptosis. J. Cell. Biol. 216, 4287–4297 (2017). · DOI · Paper page
  181. Liu, T., Jiang, L., Tavana, O. & Gu, W. The deubiquitylase OTUB1 mediates ferroptosis via stabilization of SLC7A11. Cancer Res. https://doi.org/10.1158/0008-5472.CAN-18-3037 (2019). · DOI · Paper page
  182. Yoneda, T. et al. Activation of caspase-12, an endoplastic reticulum (ER) resident caspase, through tumor necrosis factor receptor-associated factor 2-dependent mechanism in response to the ER stress. J. Biol. Chem. 276, 13935–13940 (2001). · DOI · Paper page
  183. Kalai, M. et al. Regulation of the expression and processing of caspase-12. J. Cell. Biol. 162, 457–467 (2003). · DOI
  184. Haberzettl, P. & Hill, B. G. Oxidized lipids activate autophagy in a JNK-dependent manner by stimulating the endoplasmic reticulum stress response. Redox Biol. 1, 56–64 (2013). · DOI · Paper page
  185. Barany, T. et al. Oxidative stress-related parthanatos of circulating mononuclear leukocytes in heart failure. Oxid. Med. Cell Longev. 2017, 1249614 (2017). · DOI
  186. Palladino, E. N. D., Katunga, L. A., Kolar, G. R. & Ford, D. A. 2-Chlorofatty acids: lipid mediators of neutrophil extracellular trap formation. J. Lipid Res. 59, 1424–1432 (2018). · DOI
  187. Silke, J., Rickard, J. A. & Gerlic, M. The diverse role of RIP kinases in necroptosis and inflammation. Nat. Immunol. 16, 689–697 (2015). · DOI · Paper page
  188. Polykratis, A. et al. Cutting edge: RIPK1 Kinase inactive mice are viable and protected from TNF-induced necroptosis in vivo. J. Immunol. 193, 1539–1543 (2014). · DOI · Paper page
  189. Newton, K. et al. RIPK3 deficiency or catalytically inactive RIPK1 provides greater benefit than MLKL deficiency in mouse models of inflammation and tissue injury. Cell Death Differ. 23, 1565–1576 (2016). · DOI · Paper page
  190. Berger, S. B. et al. Cutting Edge: RIP1 kinase activity is dispensable for normal development but is a key regulator of inflammation in SHARPIN-deficient mice. J. Immunol. 192, 5476–5480 (2014). · DOI · Paper page
  191. Kondylis, V., Kumari, S., Vlantis, K. & Pasparakis, M. The interplay of IKK, NF-kappaB and RIPK1 signaling in the regulation of cell death, tissue homeostasis and inflammation. Immunol. Rev. 277, 113–127 (2017). · DOI · Paper page
  192. Menon, M. B. et al. p38(MAPK)/MK2-dependent phosphorylation controls cytotoxic RIPK1 signalling in inflammation and infection. Nat. Cell Biol. 19, 1248–1259 (2017). · DOI · Paper page
  193. Dondelinger, Y. et al. MK2 phosphorylation of RIPK1 regulates TNF-mediated cell death. Nat. Cell Biol. 19, 1237–1247 (2017). · DOI · Paper page
  194. Jaco, I. et al. MK2 phosphorylates RIPK1 to prevent TNF-induced cell death. Mol. Cell 66, 698–710 e695 (2017). · DOI · Paper page
  195. Geng, J. et al. Regulation of RIPK1 activation by TAK1-mediated phosphorylation dictates apoptosis and necroptosis. Nat. Commun. 8, 359 (2017). · DOI · Paper page
  196. Wegner, K. W., Saleh, D. & Degterev, A. Complex pathologic roles of RIPK1 and RIPK3: moving beyond necroptosis. Trends Pharmacol. Sci. 38, 202–225 (2017). · DOI · Paper page
  197. Choi, J. J., Reich, C. F. 3rd & Pisetsky, D. S. Release of DNA from dead and dying lymphocyte and monocyte cell lines in vitro. Scand. J. Immunol. 60, 159–166 (2004). · DOI
  198. Chen, Q., Sun, L. & Chen, Z. J. Regulation and function of the cGAS-STING pathway of cytosolic DNA sensing. Nat. Immunol. 17, 1142–1149 (2016). · DOI · Paper page
  199. Holm, C. K. et al. Influenza A virus targets a cGAS-independent STING pathway that controls enveloped RNA viruses. Nat. Commun. 7, 10680 (2016). · DOI · Paper page
  200. Costa Franco, M. M. et al. Brucella abortus triggers a cGAS-independent STING pathway to induce host protection that involves guanylate-binding proteins and inflammasome activation. J. Immunol. 200, 607–622 (2018). · DOI

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Metadata

Authors
Tang, D., Kang, R., Berghe, T. V., Vandenabeele, P., & Kroemer, G.
Venue
Cell Research
Publisher
Springer Science and Business Media LLC
Published
2019-04-04
Volume
29
Issue
5
Pages
347-364
ISSN
  • 1001-0602 (ISSN-L)
  • 1748-7838
DOI
10.1038/s41422-019-0164-5
OpenAlex
W2935369648
Cited by
2,549
References
99
FWCI
62.52
Type
journal article
Language
en
Open access
hybrid
Licence
creativecommons.org/licenses/by/4.0 (tdm)

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Tang, D., Kang, R., Berghe, T. V., Vandenabeele, P., & Kroemer, G. (2019). The molecular machinery of regulated cell death. Cell Research. https://doi.org/10.1038/s41422-019-0164-5

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