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Linking cellular stress responses to systemic homeostasis

Nature Reviews Molecular Cell Biology volume 19, pages 731–745 (2018)Cite this article

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Abstract

Mammalian cells respond to stress by activating mechanisms that support cellular functions and hence maintain microenvironmental and organismal homeostasis. Intracellular responses to stress, their regulation and their pathophysiological implications have been extensively studied. However, little is known about the signals that emanate from stressed cells to enable a coordinated adaptive response across tissues, organs and the whole organism. Considerable evidence has now accumulated indicating that the intracellular mechanisms that are activated in response to different stresses — which include the DNA damage response, the unfolded protein response, mitochondrial stress signalling and autophagy — as well as the mechanisms ensuring the proliferative inactivation or elimination of terminally damaged cells — such as cell senescence and regulated cell death — are all coupled with the generation of signals that elicit microenvironmental and/or systemic responses. These signals, which involve changes in the surface of stressed cells and/or the secretion of soluble factors or microvesicles, generally support systemic homeostasis but can also contribute to maladaptation and disease.

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Fig. 1: Integration of cellular and systemic stress responses and their roles in the maintenance of organismal homeostasis.
Fig. 2: The DDR and UPRER in the regulation of microenvironmental and systemic homeostasis.
Fig. 3: Mitochondrial stress responses and autophagy in the regulation of microenvironmental and systemic homeostasis.
Fig. 4: Cellular senescence and RCD in the regulation of microenvironmental and systemic homeostasis.

References

  1. Fuchs, Y. & Steller, H. Live to die another way: modes of programmed cell death and the signals emanating from dying cells. Nat. Rev. Mol. Cell Biol. 16, 329–344 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Chang, H. H. Y., Pannunzio, N. R., Adachi, N. & Lieber, M. R. Non-homologous DNA end joining and alternative pathways to double-strand break repair. Nat. Rev. Mol. Cell Biol. 18, 495–506 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Hetz, C. & Papa, F. R. The unfolded protein response and cell fate control. Mol. Cell 69, 169–181 (2018).

    CAS  PubMed  Google Scholar 

  4. Shpilka, T. & Haynes, C. M. The mitochondrial UPR: mechanisms, physiological functions and implications in ageing. Nat. Rev. Mol. Cell Biol. 19, 109–120 (2018).

    CAS  PubMed  Google Scholar 

  5. Suomalainen, A. & Battersby, B. J. Mitochondrial diseases: the contribution of organelle stress responses to pathology. Nat. Rev. Mol. Cell Biol. 19, 77–92 (2018).

    CAS  PubMed  Google Scholar 

  6. Galluzzi, L., Pietrocola, F., Levine, B. & Kroemer, G. Metabolic control of autophagy. Cell 159, 1263–1276 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Galluzzi, L. et al. Molecular definitions of autophagy and related processes. EMBO J. 36, 1811–1836 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Cao, X. Self-regulation and cross-regulation of pattern-recognition receptor signalling in health and disease. Nat. Rev. Immunol. 16, 35–50 (2016).

    CAS  PubMed  Google Scholar 

  9. Neves, J., Demaria, M., Campisi, J. & Jasper, H. Of flies, mice, and men: evolutionarily conserved tissue damage responses and aging. Dev. Cell 32, 9–18 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Galluzzi, L. et al. Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018. Cell Death Differ. 25, 486–541 (2018).

    PubMed  PubMed Central  Google Scholar 

  11. Galluzzi, L., Bravo-San Pedro, J. M., Kepp, O. & Kroemer, G. Regulated cell death and adaptive stress responses. Cell. Mol. Life Sci. 73, 2405–2410 (2016).

    CAS  PubMed  Google Scholar 

  12. Yatim, N., Cullen, S. & Albert, M. L. Dying cells actively regulate adaptive immune responses. Nat. Rev. Immunol. 17, 262–275 (2017).

    CAS  PubMed  Google Scholar 

  13. He, C. et al. Exercise-induced BCL2-regulated autophagy is required for muscle glucose homeostasis. Nature 481, 511–515 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Zhang, Q. et al. Circulating mitochondrial DAMPs cause inflammatory responses to injury. Nature 464, 104–107 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Ermolaeva, M. A. & Schumacher, B. Systemic DNA damage responses: organismal adaptations to genome instability. Trends Genet. 30, 95–102 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Ribezzo, F., Shiloh, Y. & Schumacher, B. Systemic DNA damage responses in aging and diseases. Semin. Cancer Biol. 37–38, 26–35 (2016).

    PubMed  PubMed Central  Google Scholar 

  17. 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). This comprehensive review examines the molecular and cellular mechanism whereby cell death can be perceived as immunogenic by the host and the pathophysiological implication of this process.

    CAS  PubMed  Google Scholar 

  18. Gasser, S., Orsulic, S., Brown, E. J. & Raulet, D. H. The DNA damage pathway regulates innate immune system ligands of the NKG2D receptor. Nature 436, 1186–1190 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Wennerberg, E. et al. Immune recognition of irradiated cancer cells. Immunol. Rev. 280, 220–230 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Kang, T. W. et al. Senescence surveillance of pre-malignant hepatocytes limits liver cancer development. Nature 479, 547–551 (2011). This paper provides the first description of senescence surveillance as an immunological mechanism that limits oncogenesis in the liver upon the eradication of senescent hepatocytes.

    CAS  PubMed  Google Scholar 

  21. Lopez-Soto, A., Gonzalez, S., Smyth, M. J. & Galluzzi, L. Control of metastasis by NK cells. Cancer Cell 32, 135–154 (2017).

    CAS  PubMed  Google Scholar 

  22. Galluzzi, L. & Vitale, I. Oncogene-induced senescence and tumour control in complex biological systems. Cell Death Differ. 25, 1005–1006 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Dou, Z. et al. Cytoplasmic chromatin triggers inflammation in senescence and cancer. Nature 550, 402–406 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Mackenzie, K. J. et al. cGAS surveillance of micronuclei links genome instability to innate immunity. Nature 548, 461–465 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Vanpouille-Box, C. et al. DNA exonuclease Trex1 regulates radiotherapy-induced tumour immunogenicity. Nat. Commun. 8, 15618 (2017).

    PubMed  PubMed Central  Google Scholar 

  26. Harding, S. M. et al. Mitotic progression following DNA damage enables pattern recognition within micronuclei. Nature 548, 466–470 (2017). References 23–26 independently demonstrate that multiple conditions associated with DNA damage result in the accumulation of double-stranded DNA in the cytoplasm and consequent release of type I IFN upon cGAS and STING activation.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. 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).

    CAS  PubMed  Google Scholar 

  28. Galluzzi, L., Vanpouille-Box, C., Bakhoum, S. F. & Demaria, S. SnapShot: CGAS-STING signaling. Cell 173, 276–276 (2018).

    CAS  PubMed  Google Scholar 

  29. Crow, Y. J. et al. Mutations in genes encoding ribonuclease H2 subunits cause Aicardi–Goutieres syndrome and mimic congenital viral brain infection. Nat. Genet. 38, 910–916 (2006).

    CAS  PubMed  Google Scholar 

  30. Crow, Y. J. et al. Mutations in the gene encoding the 3'–5' DNA exonuclease TREX1 cause Aicardi–Goutieres syndrome at the AGS1 locus. Nat. Genet. 38, 917–920 (2006).

    CAS  PubMed  Google Scholar 

  31. King, K. R. et al. IRF3 and type I interferons fuel a fatal response to myocardial infarction. Nat. Med. 23, 1481–1487 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Dewan, M. Z. et al. Fractionated but not single-dose radiotherapy induces an immune-mediated abscopal effect when combined with anti-CTLA-4 antibody. Clin. Cancer Res. 15, 5379–5388 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Dewan, M. Z. et al. Synergy of topical toll-like receptor 7 agonist with radiation and low-dose cyclophosphamide in a mouse model of cutaneous breast cancer. Clin. Cancer Res. 18, 6668–6678 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Reijns, M. A. et al. Enzymatic removal of ribonucleotides from DNA is essential for mammalian genome integrity and development. Cell 149, 1008–1022 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Stephens, P. J. et al. Massive genomic rearrangement acquired in a single catastrophic event during cancer development. Cell 144, 27–40 (2011). This paper characterizes chromothripsis as a single catastrophic event affecting one or a few chromosomes (or fragments thereof) that simultaneously generates tens of hundreds of genomic rearrangements.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Vitale, I., Manic, G., Senovilla, L., Kroemer, G. & Galluzzi, L. Karyotypic aberrations in oncogenesis and cancer therapy. Trends Cancer 1, 124–135 (2015).

    PubMed  Google Scholar 

  37. Valent, A., Penault-Llorca, F., Cayre, A. & Kroemer, G. Change in HER2 (ERBB2) gene status after taxane-based chemotherapy for breast cancer: polyploidization can lead to diagnostic pitfalls with potential impact for clinical management. Cancer Genet. 206, 37–41 (2013).

    CAS  PubMed  Google Scholar 

  38. Mitchison, T. J., Pineda, J., Shi, J. & Florian, S. Is inflammatory micronucleation the key to a successful anti-mitotic cancer drug? Open Biol. 7, 170182 (2017).

    PubMed  PubMed Central  Google Scholar 

  39. Xia, T., Konno, H., Ahn, J. & Barber, G. N. Deregulation of STING signaling in colorectal carcinoma constrains DNA damage responses and correlates with tumorigenesis. Cell Rep. 14, 282–297 (2016).

    CAS  PubMed  Google Scholar 

  40. Bartsch, K. et al. Absence of RNase H2 triggers generation of immunogenic micronuclei removed by autophagy. Hum. Mol. Genet. 26, 3960–3972 (2017).

    CAS  PubMed  Google Scholar 

  41. Dou, Z. et al. Autophagy mediates degradation of nuclear lamina. Nature 527, 105–109 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Rello-Varona, S. et al. Autophagic removal of micronuclei. Cell Cycle 11, 170–176 (2012).

    CAS  PubMed  Google Scholar 

  43. Rybstein, M. D., Bravo-San Pedro, J. M., Kroemer, G. & Galluzzi, L. The autophagic network and cancer. Nat. Cell Biol. 20, 243–251 (2018).

    CAS  PubMed  Google Scholar 

  44. Dikic, I. & Elazar, Z. Mechanism and medical implications of mammalian autophagy. Nat. Rev. Mol. Cell Biol. 19, 349–364 (2018).

    CAS  PubMed  Google Scholar 

  45. Ermolaeva, M. A. et al. DNA damage in germ cells induces an innate immune response that triggers systemic stress resistance. Nature 501, 416–420 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Peng, Y. et al. Cysteine protease cathepsin B mediates radiation-induced bystander effects. Nature 547, 458–462 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Recklies, A. D., Tiltman, K. J., Stoker, T. A. & Poole, A. R. Secretion of proteinases from malignant and nonmalignant human breast tissue. Cancer Res. 40, 550–556 (1980).

    CAS  PubMed  Google Scholar 

  48. Shree, T. et al. Macrophages and cathepsin proteases blunt chemotherapeutic response in breast cancer. Genes Dev. 25, 2465–2479 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Bian, B. et al. Cathepsin B promotes colorectal tumorigenesis, cell invasion, and metastasis. Mol. Carcinog. 55, 671–687 (2016).

    CAS  PubMed  Google Scholar 

  50. Moon, H. Y. et al. Running-induced systemic cathepsin B secretion is associated with memory function. Cell Metab. 24, 332–340 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Frakes, A. E. & Dillin, A. The UPR(ER): Sensor and coordinator of organismal homeostasis. Mol. Cell 66, 761–771 (2017).

    CAS  PubMed  Google Scholar 

  52. Mami, I. et al. A novel extrinsic pathway for the unfolded protein response in the kidney. J. Am. Soc. Nephrol. 27, 2670–2683 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Vecchi, C. et al. ER stress controls iron metabolism through induction of hepcidin. Science 325, 877–880 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Hosomi, S. et al. Intestinal epithelial cell endoplasmic reticulum stress promotes MULT1 up-regulation and NKG2D-mediated inflammation. J. Exp. Med. 214, 2985–2997 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Miyake, M. et al. Skeletal muscle-specific eukaryotic translation initiation factor 2alpha phosphorylation controls amino acid metabolism and fibroblast growth factor 21-mediated non-cell-autonomous energy metabolism. FASEB J. 30, 798–812 (2016).

    CAS  PubMed  Google Scholar 

  56. Bohnert, K. R., McMillan, J. D. & Kumar, A. Emerging roles of ER stress and unfolded protein response pathways in skeletal muscle health and disease. J. Cell. Physiol. 233, 67–78 (2018).

    CAS  PubMed  Google Scholar 

  57. Ozcan, L. et al. Endoplasmic reticulum stress plays a central role in development of leptin resistance. Cell Metab. 9, 35–51 (2009).

    CAS  PubMed  Google Scholar 

  58. Williams, K. W. et al. Xbp1s in Pomc neurons connects ER stress with energy balance and glucose homeostasis. Cell Metab. 20, 471–482 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Taylor, R. C. & Dillin, A. XBP-1 is a cell-nonautonomous regulator of stress resistance and longevity. Cell 153, 1435–1447 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Guan, B. J. et al. A unique ISR program determines cellular responses to chronic stress. Mol. Cell 68, 885–900 e886 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Sundaram, A., Plumb, R., Appathurai, S. & Mariappan, M. The Sec61 translocon limits IRE1alpha signaling during the unfolded protein response. eLife 6, 27187 (2017).

    Google Scholar 

  62. Rodvold, J. J. et al. Intercellular transmission of the unfolded protein response promotes survival and drug resistance in cancer cells. Sci. Signal. 10, aah7177 (2017). The authors of this article demonstrate that the UPR ER can be transmitted between cancer cells in a process with important implications for tumour progression and response to treatment that they term ‘transmissible ER stress’.

    Google Scholar 

  63. Bezu, L. et al. eIF2alpha phosphorylation is pathognomonic for immunogenic cell death. Cell Death Differ. (2018).

  64. Panaretakis, T. et al. Mechanisms of pre-apoptotic calreticulin exposure in immunogenic cell death. EMBO J. 28, 578–590 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Fucikova, J. et al. Calreticulin expression in human non-small cell lung cancers correlates with increased accumulation of antitumor immune cells and favorable prognosis. Cancer Res. 76, 1746–1756 (2016).

    CAS  PubMed  Google Scholar 

  66. Fucikova, J. et al. Calreticulin exposure by malignant blasts correlates with robust anticancer immunity and improved clinical outcome in AML patients. Blood 128, 3113–3124 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Osman, R., Tacnet-Delorme, P., Kleman, J. P., Millet, A. & Frachet, P. Calreticulin release at an early stage of death modulates the clearance by macrophages of apoptotic cells. Front. Immunol. 8, 1034 (2017).

    PubMed  PubMed Central  Google Scholar 

  68. He, X. Y. et al. Calreticulin fragment 39–272 promotes B16 melanoma malignancy through myeloid-derived suppressor cells in vivo. Front. Immunol. 8, 1306 (2017).

    PubMed  PubMed Central  Google Scholar 

  69. De, I., Dogra, N. & Singh, S. The mitochondrial unfolded protein response: role in cellular homeostasis and disease. Curr. Mol. Med. 17, 587–597 (2017).

    CAS  PubMed  Google Scholar 

  70. Moehle, E. A., Shen, K. & Dillin, A. Mitochondrial proteostasis in the context of cellular and organismal health and aging. J. Biol. Chem. https://doi.org/10.1074/jbc.TM117.000893 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  71. Tian, Y., Merkwirth, C. & Dillin, A. Mitochondrial UPR: a double-edged sword. Trends Cell Biol. 26, 563–565 (2016).

    CAS  PubMed  Google Scholar 

  72. Melber, A. & Haynes, C. M. UPR(mt) regulation and output: a stress response mediated by mitochondrial-nuclear communication. Cell Res. 28, 281–295 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Owusu-Ansah, E., Song, W. & Perrimon, N. Muscle mitohormesis promotes longevity via systemic repression of insulin signaling. Cell 155, 699–712 (2013).

    CAS  PubMed  Google Scholar 

  74. Wang, X. & Auwerx, J. Systems phytohormone responses to mitochondrial proteotoxic stress. Mol. Cell 68, 540–551.e545 (2017).

    CAS  PubMed  Google Scholar 

  75. Shao, L. W., Niu, R. & Liu, Y. Neuropeptide signals cell non-autonomous mitochondrial unfolded protein response. Cell Res. 26, 1182–1196 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Berendzen, K. M. et al. Neuroendocrine coordination of mitochondrial stress signaling and proteostasis. Cell 166, 1553–1563.e1510 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Pellegrino, M. W. et al. Mitochondrial UPR-regulated innate immunity provides resistance to pathogen infection. Nature 516, 414–417 (2014). The authors of this paper show that the UPR mt in C. elegans has a major impact on the systemic response to bacterial infection by favouring the secretion of lysozyme and other antimicrobial peptides.

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Pellegrino, M. W., Nargund, A. M. & Haynes, C. M. Signaling the mitochondrial unfolded protein response. Biochim. Biophys. Acta 1833, 410–416 (2013).

    CAS  PubMed  Google Scholar 

  79. Nargund, A. M., Fiorese, C. J., Pellegrino, M. W., Deng, P. & Haynes, C. M. Mitochondrial and nuclear accumulation of the transcription factor ATFS-1 promotes OXPHOS recovery during the UPR(mt). Mol. Cell 58, 123–133 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Kim, K. H. et al. Autophagy deficiency leads to protection from obesity and insulin resistance by inducing Fgf21 as a mitokine. Nat. Med. 19, 83–92 (2013).

    CAS  PubMed  Google Scholar 

  81. Chung, H. K. et al. Growth differentiation factor 15 is a myomitokine governing systemic energy homeostasis. J. Cell Biol. 216, 149–165 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Hsu, J. Y. et al. Non-homeostatic body weight regulation through a brainstem-restricted receptor for GDF15. Nature 550, 255–259 (2017).

    PubMed  Google Scholar 

  83. Fujita, Y., Taniguchi, Y., Shinkai, S., Tanaka, M. & Ito, M. Secreted growth differentiation factor 15 as a potential biomarker for mitochondrial dysfunctions in aging and age-related disorders. Geriatr. Gerontol. Int. 16 (Suppl. 1), 17–29 (2016).

    PubMed  Google Scholar 

  84. Adela, R. & Banerjee, S. K. GDF-15 as a target and biomarker for diabetes and cardiovascular diseases: a translational prospective. J. Diabetes Res. 2015, 490842 (2015).

    PubMed  PubMed Central  Google Scholar 

  85. Xiong, Y. et al. Long-acting MIC-1/GDF15 molecules to treat obesity: evidence from mice to monkeys. Sci. Transl Med. 9, aan8732 (2017).

    Google Scholar 

  86. Kim, S. J., Xiao, J., Wan, J., Cohen, P. & Yen, K. Mitochondrially derived peptides as novel regulators of metabolism. J. Physiol. 595, 6613–6621 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Gong, Z. et al. Humanin is an endogenous activator of chaperone-mediated autophagy. J. Cell Biol. 217, 635–647 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Han, K., Jia, N., Zhong, Y. & Shang, X. S14G-humanin alleviates insulin resistance and increases autophagy in neurons of APP/PS1 transgenic mouse. J. Cell. Biochem. 119, 3111–3117 (2017).

    PubMed  Google Scholar 

  89. Gidlund, E. K. et al. Humanin skeletal muscle protein levels increase after resistance training in men with impaired glucose metabolism. Physiol. Rep. 4, e13063 (2016).

    PubMed  PubMed Central  Google Scholar 

  90. Lee, C. et al. The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell Metab. 21, 443–454 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Zhai, D. et al. MOTS-c peptide increases survival and decreases bacterial load in mice infected with MRSA. Mol. Immunol. 92, 151–160 (2017).

    CAS  PubMed  Google Scholar 

  92. Cobb, L. J. et al. Naturally occurring mitochondrial-derived peptides are age-dependent regulators of apoptosis, insulin sensitivity, and inflammatory markers. Aging (Albany NY) 8, 796–809 (2016).

    CAS  Google Scholar 

  93. Galluzzi, L., Kepp, O. & Kroemer, G. Mitochondria: master regulators of danger signalling. Nat. Rev. Mol. Cell Biol. 13, 780–788 (2012).

    CAS  PubMed  Google Scholar 

  94. White, M. J. et al. Apoptotic caspases suppress mtDNA-induced STING-mediated type I IFN production. Cell 159, 1549–1562 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Rongvaux, A. et al. Apoptotic caspases prevent the induction of type I interferons by mitochondrial DNA. Cell 159, 1563–1577 (2014). References 94 and 95 independently demonstrate that MOMP generally allows for the release of mtDNA into the cytosol, resulting in type I IFN production by cGAS and STING unless apoptotic caspases are active.

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Zhou, R., Yazdi, A. S., Menu, P. & Tschopp, J. A role for mitochondria in NLRP3 inflammasome activation. Nature 469, 221–225 (2011).

    CAS  PubMed  Google Scholar 

  97. Nakahira, K. et al. Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome. Nat. Immunol. 12, 222–230 (2011).

    CAS  PubMed  Google Scholar 

  98. Zhong, Z. et al. NF-kappaB restricts inflammasome activation via elimination of damaged mitochondria. Cell 164, 896–910 (2016). References 97 and 98 show that NF-κB-driven mitophagy mediates robust anti-inflammatory effects by disposing of damaged mitochondria before they release endogenous inflammasome activators.

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Zhou, R., Tardivel, A., Thorens, B., Choi, I. & Tschopp, J. Thioredoxin-interacting protein links oxidative stress to inflammasome activation. Nat. Immunol. 11, 136–140 (2010).

    CAS  PubMed  Google Scholar 

  100. Al-Mehdi, A. B. et al. Perinuclear mitochondrial clustering creates an oxidant-rich nuclear domain required for hypoxia-induced transcription. Sci. Signal 5, ra47 (2012).

    PubMed  PubMed Central  Google Scholar 

  101. Dieude, M. et al. Cardiolipin binds to CD1d and stimulates CD1d-restricted gammadelta T cells in the normal murine repertoire. J. Immunol. 186, 4771–4781 (2011).

    CAS  PubMed  Google Scholar 

  102. Vance, J. E. MAM (mitochondria-associated membranes) in mammalian cells: lipids and beyond. Biochim. Biophys. Acta 1841, 595–609 (2014).

    CAS  PubMed  Google Scholar 

  103. Levy, J. M. M., Towers, C. G. & Thorburn, A. Targeting autophagy in cancer. Nat. Rev. Cancer 17, 528–542 (2017).

    CAS  PubMed  Google Scholar 

  104. Galluzzi, L., Bravo-San Pedro, J. M., Levine, B., Green, D. R. & Kroemer, G. Pharmacological modulation of autophagy: therapeutic potential and persisting obstacles. Nat. Rev. Drug Discov. 16, 487–511 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Martinez-Outschoorn, U. E., Peiris-Pages, M., Pestell, R. G., Sotgia, F. & Lisanti, M. P. Cancer metabolism: a therapeutic perspective. Nat. Rev. Clin. Oncol. 14, 11–31 (2017).

    CAS  PubMed  Google Scholar 

  106. Capparelli, C. et al. Autophagy and senescence in cancer-associated fibroblasts metabolically supports tumor growth and metastasis via glycolysis and ketone production. Cell Cycle 11, 2285–2302 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Sousa, C. M. et al. Pancreatic stellate cells support tumour metabolism through autophagic alanine secretion. Nature 536, 479–483 (2016). This study is the first demonstration that autophagic responses in pancreatic stellate cells allow for the release of alanine in the tumour microenvironment, where it can be taken up by malignant cells to support tumour progression.

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Martin, S. et al. An autophagy-driven pathway of ATP secretion supports the aggressive phenotype of BRAF(V600E) inhibitor-resistant metastatic melanoma cells. Autophagy 13, 1512–1527 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Qu, X. et al. Autophagy gene-dependent clearance of apoptotic cells during embryonic development. Cell 128, 931–946 (2007).

    CAS  PubMed  Google Scholar 

  110. Michaud, M. et al. Autophagy-dependent anticancer immune responses induced by chemotherapeutic agents in mice. Science 334, 1573–1577 (2011). The authors of this study report that the immunogenicity of anthracycline-driven cell death obligatorily relies on the activation of autophagic responses that precede RCD and enable robust ATP release.

    CAS  PubMed  Google Scholar 

  111. Elliott, M. R. et al. Nucleotides released by apoptotic cells act as a find-me signal to promote phagocytic clearance. Nature 461, 282–286 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Buque, A. et al. Trial Watch-Small molecules targeting the immunological tumor microenvironment for cancer therapy. Oncoimmunology 5, e1149674 (2016).

    PubMed  PubMed Central  Google Scholar 

  113. Galluzzi, L., Bravo-San Pedro, J. M., Demaria, S., Formenti, S. C. & Kroemer, G. Activating autophagy to potentiate immunogenic chemotherapy and radiation therapy. Nat. Rev. Clin. Oncol. 14, 247–258 (2017).

    CAS  PubMed  Google Scholar 

  114. Martinez-Lopez, N. et al. System-wide benefits of intermeal fasting by autophagy. Cell Metab. 26, 856–871 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Dupont, N. et al. Autophagy-based unconventional secretory pathway for extracellular delivery of IL-1beta. EMBO J. 30, 4701–4711 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Loomis, W. F., Behrens, M. M., Williams, M. E. & Anjard, C. Pregnenolone sulfate and cortisol induce secretion of acyl-CoA-binding protein and its conversion into endozepines from astrocytes. J. Biol. Chem. 285, 21359–21365 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Claude-Taupin, A., Jia, J., Mudd, M. & Deretic, V. Autophagy’s secret life: secretion instead of degradation. Essays Biochem. 61, 637–647 (2017).

    PubMed  Google Scholar 

  118. Zhang, M., Kenny, S. J., Ge, L., Xu, K. & Schekman, R. Translocation of interleukin-1β into a vesicle intermediate in autophagy-mediated secretion. eLife 4, 11205 (2015).

    Google Scholar 

  119. Kimura, T. et al. Dedicated SNAREs and specialized TRIM cargo receptors mediate secretory autophagy. EMBO J. 36, 42–60 (2017).

    CAS  PubMed  Google Scholar 

  120. Shi, C. S. et al. Activation of autophagy by inflammatory signals limits IL-1beta production by targeting ubiquitinated inflammasomes for destruction. Nat. Immunol. 13, 255–263 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Harris, J. et al. Autophagy controls IL-1beta secretion by targeting pro-IL-1beta for degradation. J. Biol. Chem. 286, 9587–9597 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Eisenberg, T. et al. Cardioprotection and lifespan extension by the natural polyamine spermidine. Nat. Med. 22, 1428–1438 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Ip, W. K. E., Hoshi, N., Shouval, D. S., Snapper, S. & Medzhitov, R. Anti-inflammatory effect of IL-10 mediated by metabolic reprogramming of macrophages. Science 356, 513–519 (2017). This study is the first demonstration that the anti-inflammatory effects of IL-10 result (at least in part) from the activation of a mitophagic response that limits inflammasome activation in macrophages.

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Esteban-Martinez, L. et al. Programmed mitophagy is essential for the glycolytic switch during cell differentiation. EMBO J. 36, 1688–1706 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Bel, S. et al. Paneth cells secrete lysozyme via secretory autophagy during bacterial infection of the intestine. Science 357, 1047–1052 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. McHugh, D. & Gil, J. Senescence and aging: causes, consequences, and therapeutic avenues. J. Cell Biol. 217, 65–77 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Hoare, M. et al. NOTCH1 mediates a switch between two distinct secretomes during senescence. Nat. Cell Biol. 18, 979–992 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Morancho, B., Martinez-Barriocanal, A., Villanueva, J. & Arribas, J. Role of ADAM17 in the non-cell autonomous effects of oncogene-induced senescence. Breast Cancer Res. 17, 106 (2015).

    PubMed  PubMed Central  Google Scholar 

  129. Gluck, S. et al. Innate immune sensing of cytosolic chromatin fragments through cGAS promotes senescence. Nat. Cell Biol. 19, 1061–1070 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Ishikawa, H. & Barber, G. N. STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling. Nature 455, 674–678 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Ishikawa, H., Ma, Z. & Barber, G. N. STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity. Nature 461, 788–792 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Katlinskaya, Y. V. et al. Suppression of type I interferon signaling overcomes oncogene-induced senescence and mediates melanoma development and progression. Cell Rep. 15, 171–180 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Acosta, J. C. et al. Chemokine signaling via the CXCR2 receptor reinforces senescence. Cell 133, 1006–1018 (2008).

    CAS  PubMed  Google Scholar 

  134. Kuilman, T. et al. Oncogene-induced senescence relayed by an interleukin-dependent inflammatory network. Cell 133, 1019–1031 (2008).

    CAS  PubMed  Google Scholar 

  135. Wajapeyee, N., Serra, R. W., Zhu, X., Mahalingam, M. & Green, M. R. Oncogenic BRAF induces senescence and apoptosis through pathways mediated by the secreted protein IGFBP7. Cell 132, 363–374 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Lehmann, B. D. et al. Senescence-associated exosome release from human prostate cancer cells. Cancer Res. 68, 7864–7871 (2008).

    CAS  PubMed  Google Scholar 

  137. Lopez-Otin, C., Blasco, M. A., Partridge, L., Serrano, M. & Kroemer, G. The hallmarks of aging. Cell 153, 1194–1217 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. Baker, D. J. et al. Naturally occurring p16(Ink4a)-positive cells shorten healthy lifespan. Nature 530, 184–189 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Baker, D. J. et al. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature 479, 232–236 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. Baar, M. P. et al. Targeted apoptosis of senescent cells restores tissue homeostasis in response to chemotoxicity and aging. Cell 169, 132–147.e116 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  141. Farr, J. N. et al. Targeting cellular senescence prevents age-related bone loss in mice. Nat. Med. 23, 1072–1079 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. Xu, M. et al. Targeting senescent cells enhances adipogenesis and metabolic function in old age. Elife 4, e12997 (2015).

    PubMed  PubMed Central  Google Scholar 

  143. Xu, M. et al. JAK inhibition alleviates the cellular senescence-associated secretory phenotype and frailty in old age. Proc. Natl Acad. Sci. USA 112, E6301–E6310 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. Rodier, F. & Campisi, J. Four faces of cellular senescence. J. Cell Biol. 192, 547–556 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  145. Demaria, M. et al. An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA. Dev. Cell 31, 722–733 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  146. Iannello, A., Thompson, T. W., Ardolino, M., Lowe, S. W. & Raulet, D. H. p53-dependent chemokine production by senescent tumor cells supports NKG2D-dependent tumor elimination by natural killer cells. J. Exp. Med. 210, 2057–2069 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  147. Takasugi, M. et al. Small extracellular vesicles secreted from senescent cells promote cancer cell proliferation through EphA2. Nat. Commun. 8, 15729 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. Uderhardt, S. et al. 12/15-lipoxygenase orchestrates the clearance of apoptotic cells and maintains immunologic tolerance. Immunity 36, 834–846 (2012).

    CAS  PubMed  Google Scholar 

  149. Roberts, A. W. et al. Tissue-resident macrophages are locally programmed for silent clearance of apoptotic cells. Immunity 47, 913–927 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  150. Mistry, P. & Kaplan, M. J. Cell death in the pathogenesis of systemic lupus erythematosus and lupus nephritis. Clin. Immunol. 185, 59–73 (2017).

    CAS  PubMed  Google Scholar 

  151. Huang, Q. et al. Caspase 3-mediated stimulation of tumor cell repopulation during cancer radiotherapy. Nat. Med. 17, 860–866 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. Zelenay, S. et al. Cyclooxygenase-dependent tumor growth through evasion of immunity. Cell 162, 1257–1270 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  153. Suzuki, J., Denning, D. P., Imanishi, E., Horvitz, H. R. & Nagata, S. Xk-related protein 8 and CED-8 promote phosphatidylserine exposure in apoptotic cells. Science 341, 403–406 (2013).

    CAS  PubMed  Google Scholar 

  154. Segawa, K. et al. Caspase-mediated cleavage of phospholipid flippase for apoptotic phosphatidylserine exposure. Science 344, 1164–1168 (2014).

    CAS  PubMed  Google Scholar 

  155. Fadok, V. A. et al. A receptor for phosphatidylserine-specific clearance of apoptotic cells. Nature 405, 85–90 (2000).

    CAS  PubMed  Google Scholar 

  156. Li, M. O., Sarkisian, M. R., Mehal, W. Z., Rakic, P. & Flavell, R. A. Phosphatidylserine receptor is required for clearance of apoptotic cells. Science 302, 1560–1563 (2003). References 155 and 156 characterize the receptor for PtdSer and its critical importance for the silent removal of apoptotic cells in the context of PCD.

    CAS  PubMed  Google Scholar 

  157. Martinez, J. et al. Noncanonical autophagy inhibits the autoinflammatory, lupus-like response to dying cells. Nature 533, 115–119 (2016). The authors of this study demonstrate that defects in LC3-associated phagocytosis cause deficient removal of dead cells by phagocytosis, culminating in an autoimmune disease similar to SLE, at least in mice.

    CAS  PubMed  PubMed Central  Google Scholar 

  158. Zitvogel, L., Galluzzi, L., Kepp, O., Smyth, M. J. & Kroemer, G. Type I interferons in anticancer immunity. Nat. Rev. Immunol. 15, 405–414 (2015).

    CAS  PubMed  Google Scholar 

  159. Franz, K. M. & Kagan, J. C. Innate immune receptors as competitive determinants of cell fate. Mol. Cell 66, 750–760 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  160. Zanoni, I., Tan, Y., Di Gioia, M., Springstead, J. R. & Kagan, J. C. By capturing inflammatory lipids released from dying cells, the receptor CD14 induces inflammasome-dependent phagocyte hyperactivation. Immunity 47, 697–709 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  161. Vacchelli, E. et al. Chemotherapy-induced antitumor immunity requires formyl peptide receptor 1. Science 350, 972–978 (2015).

    CAS  PubMed  Google Scholar 

  162. Jorgensen, I., Rayamajhi, M. & Miao, E. A. Programmed cell death as a defence against infection. Nat. Rev. Immunol. 17, 151–164 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  163. Shi, J. et al. Inflammatory caspases are innate immune receptors for intracellular LPS. Nature 514, 187–192 (2014).

    CAS  PubMed  Google Scholar 

  164. Wang, Y. et al. Chemotherapy drugs induce pyroptosis through caspase-3 cleavage of a gasdermin. Nature 547, 99–103 (2017). This paper provides the first description of a pyroptotic variant of RCD that depends on CASP3 and GSDME, rather than on inflammatory caspases and GDSMD, which might contribute to the side effects of chemotherapy.

    CAS  PubMed  Google Scholar 

  165. Eil, R. et al. Ionic immune suppression within the tumour microenvironment limits T cell effector function. Nature 537, 539–543 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  166. Galluzzi, L., Kepp, O., Chan, F. K. & Kroemer, G. Necroptosis: mechanisms and relevance to disease. Annu. Rev. Pathol. 12, 103–130 (2017).

    CAS  PubMed  Google Scholar 

  167. 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).

    CAS  PubMed  Google Scholar 

  168. Yang, H. et al. Contribution of RIP3 and MLKL to immunogenic cell death signaling in cancer chemotherapy. Oncoimmunology 5, e1149673 (2016).

    PubMed  PubMed Central  Google Scholar 

  169. Conos, S. A. et al. Active MLKL triggers the NLRP3 inflammasome in a cell-intrinsic manner. Proc. Natl Acad. Sci. USA 114, E961–E969 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  170. Vince, J. E. et al. Inhibitor of apoptosis proteins limit RIP3 kinase-dependent interleukin-1 activation. Immunity 36, 215–227 (2012).

    CAS  PubMed  Google Scholar 

  171. Yatim, N. et al. RIPK1 and NF-kappaB signaling in dying cells determines cross-priming of CD8+ T cells. Science 350, 328–334 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  172. Aaes, T. L. et al. Vaccination with necroptotic cancer cells induces efficient anti-tumor immunity. Cell Rep. 15, 274–287 (2016). References 171 and 172 demonstrate that RIPK3-driven necroptotic cell death is immunogenic and is accompanied by the activation of an NF-κB-dependent transcriptional response.

    CAS  PubMed  Google Scholar 

  173. Kepp, O. et al. Consensus guidelines for the detection of immunogenic cell death. Oncoimmunology 3, e955691 (2014).

    PubMed  PubMed Central  Google Scholar 

  174. Sistigu, A. et al. Cancer cell-autonomous contribution of type I interferon signaling to the efficacy of chemotherapy. Nat. Med. 20, 1301–1309 (2014).

    CAS  PubMed  Google Scholar 

  175. Giampazolias, E. et al. Mitochondrial permeabilization engages NF-κB-dependent anti-tumour activity under caspase deficiency. Nat. Cell Biol. 19, 1116–1129 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  176. Galluzzi, L., Lopez-Soto, A., Kumar, S. & Kroemer, G. Caspases connect cell-death signaling to organismal homeostasis. Immunity 44, 221–231 (2016).

    CAS  PubMed  Google Scholar 

  177. Senovilla, L. et al. An immunosurveillance mechanism controls cancer cell ploidy. Science 337, 1678–1684 (2012).

    CAS  PubMed  Google Scholar 

  178. Galluzzi, L. et al. Essential versus accessory aspects of cell death: recommendations of the NCCD 2015. Cell Death Differ. 22, 58–73 (2015).

    CAS  PubMed  Google Scholar 

  179. Xu, X., Zhao, Y., Kirkman, E. & Lin, X. Secreted Acb1 contributes to the yeast-to-hypha transition in Cryptococcus neoformans. Appl. Environ. Microbiol. 82, 1069–1079 (2015).

    PubMed  Google Scholar 

  180. Vitale, I., Manic, G., De Maria, R., Kroemer, G. & Galluzzi, L. DNA damage in stem cells. Mol. Cell 66, 306–319 (2017).

    CAS  PubMed  Google Scholar 

  181. Luo, S., Baumeister, P., Yang, S., Abcouwer, S. F. & Lee, A. S. Induction of Grp78/BiP by translational block: activation of the Grp78 promoter by ATF4 through and upstream ATF/CRE site independent of the endoplasmic reticulum stress elements. J. Biol. Chem. 278, 37375–37385 (2003).

    CAS  PubMed  Google Scholar 

  182. Lee, A. H., Iwakoshi, N. N. & Glimcher, L. H. XBP-1 regulates a subset of endoplasmic reticulum resident chaperone genes in the unfolded protein response. Mol. Cell. Biol. 23, 7448–7459 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  183. Haze, K., Yoshida, H., Yanagi, H., Yura, T. & Mori, K. Mammalian transcription factor ATF6 is synthesized as a transmembrane protein and activated by proteolysis in response to endoplasmic reticulum stress. Mol. Biol. Cell 10, 3787–3799 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  184. Johannes, G. & Sarnow, P. Cap-independent polysomal association of natural mRNAs encoding c-myc, BiP, and eIF4G conferred by internal ribosome entry sites. RNA 4, 1500–1513 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  185. Novoa, I., Zeng, H., Harding, H. P. & Ron, D. Feedback inhibition of the unfolded protein response by GADD34-mediated dephosphorylation of eIF2alpha. J. Cell Biol. 153, 1011–1022 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  186. Zinszner, H. et al. CHOP is implicated in programmed cell death in response to impaired function of the endoplasmic reticulum. Genes Dev. 12, 982–995 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  187. Galluzzi, L., Bravo-San Pedro, J. M. & Kroemer, G. Organelle-specific initiation of cell death. Nat. Cell Biol. 16, 728–736 (2014).

    CAS  PubMed  Google Scholar 

  188. Sica, V. et al. Organelle-specific initiation of autophagy. Mol. Cell 59, 522–539 (2015).

    CAS  PubMed  Google Scholar 

  189. Stolz, A., Ernst, A. & Dikic, I. Cargo recognition and trafficking in selective autophagy. Nat. Cell Biol. 16, 495–501 (2014).

    CAS  PubMed  Google Scholar 

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Acknowledgements

The authors apologize to the authors of several high-quality articles dealing with the links between intracellular stress responses and the regulation of organismal homeostasis that were not able to be discussed and cited owing to space limitations. L.G. is supported by a start-up grant from the Department of Radiation Oncology at Weill Cornell Medicine (New York, NY, USA), by industrial grants from Lytix (Oslo, Norway) and Phosplatin (New York, NY, USA), and by donations from Sotio a.s. (Prague, Czech Republic), the Luke Heller TECPR2 Foundation (Boston, MA, USA) and Phosplatin (New York, NY, USA). G.K. is supported by the Ligue contre le Cancer Comité de Charente-Maritime (Équipe Labellisée); the Agence National de la Recherche (ANR) — Projets Blancs; ANR under the framework of E-Rare-2, the ERA-Net for Research on Rare Diseases; the Association pour la Recherche sur le Cancer (ARC); Cancéropôle Ile-de-France; Chancelerie des Universités de Paris (Legs Poix), the Fondation pour la Recherche Médicale (FRM); a donation by Elior; the European Commission (ArtForce); the European Research Council (ERC); the Fondation Carrefour; the Institut National du Cancer (INCa); INSERM (HTE); the Institut Universitaire de France; the LeDucq Foundation; the LabEx Immuno-Oncology; RHU Torino Lumière; the Seerave Foundation; the SIRIC Stratified Oncology Cell DNA Repair and Tumour Immune Elimination (SOCRATE); and the SIRIC Cancer Research and Personalized Medicine (CARPEM). L.G.’s homepage: http://www.galluzzilab.com. G.K.’s homepage: http://www.kroemerlab.com.

Reviewer information

Nature Reviews Molecular Cell Biology thanks C. Hetz, B. Schumacher and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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Author notes

  1. These authors share senior authorship: Lorenzo Galluzzi, Guido Kroemer.

Authors and Affiliations

  1. Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA

    Lorenzo Galluzzi & Takahiro Yamazaki

  2. Sandra and Edward Meyer Cancer Center, New York, NY, USA

    Lorenzo Galluzzi

  3. Université Paris Descartes/Paris V, Paris, France

    Lorenzo Galluzzi & Guido Kroemer

  4. Université Pierre et Marie Curie/Paris VI, Paris, France

    Guido Kroemer

  5. Equipe 11 Labellisée Ligue contre le Cancer, Centre de Recherche des Cordeliers, Paris, France

    Guido Kroemer

  6. INSERM, U1138, Paris, France

    Guido Kroemer

  7. Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Institute, Villejuif, France

    Guido Kroemer

  8. Department of Women’s and Children’s Health, Karolinska University Hospital, Stockholm, Sweden

    Guido Kroemer

  9. Pôle de Biologie, Hopitâl Européen George Pompidou, AP-HP, Paris, France

    Guido Kroemer

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All authors researched data for the article, wrote the article and edited the manuscript. L.G. and G.K. contributed to discussion of the content before submission.

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Glossary

Pattern recognition receptors

Evolutionarily conserved receptors that elicit inflammation and innate immunity upon recognition of conserved microbial products or endogenous danger signals.

Regulated cell death

(RCD). Variant of cell death that relies on a dedicated, genetically encoded machinery and hence can be delayed or accelerated with pharmacological or genetic interventions.

Cell cycle checkpoints

Control mechanisms that ensure the progression of eukaryotic cells along the cell cycle only in the presence of favourable conditions.

Immunogenicity

The ability to trigger an immune response, resulting from antigenicity (the property of being recognized by immune cells) and adjuvanticity (the property of delivering activating signals to immune cells).

Natural killer (NK) cells

A group of cells from the innate lymphoid immune system that can mediate cytotoxic functions independent of antigen recognition.

Major histocompatibility complex

(MHC). Set of cell surface proteins essential for the immune system to recognize foreign molecules in vertebrates.

Abscopal responses

Measurable reductions in the size of a non-irradiated tumour or metastasis thereof following the irradiation of another lesion.

Hypofractionated irradiation

The delivery of radiation therapy in a few fractions, each with a larger dose than the standard 1.8 or 2 Gy.

Micronuclei

Small enveloped structures that encompass chromosomes of fragments thereof that are not incorporated into one of the daughter nuclei during mitosis.

Chromothripsis

A process whereby up to thousands of clustered chromosomal rearrangements occur in a single event in localized genomic regions affecting one or a few chromosomes.

Proteostasis

The maintenance of protein homeostasis within a defined organelle, cell or tissue, which involves correct protein synthesis, folding, distribution and degradation.

Myokine

One of several small proteins or proteoglycans that are released by myocytes upon contraction to mediate autocrine, paracrine or endocrine effects.

Nuclear factor-κB (NF-κB) signalling

Biological output of NF-κB-dependent transcription, generally involving a robust pro-inflammatory component.

Hepcidin antimicrobial peptide

(HAMP). Key negative regulator of circulating iron availability in mammals, promoting a state of accrued bacterial resistance.

Brown adipose tissue

Highly specialized adipose tissue, the main function of which is to produce heat (thermogenesis).

Dendritic cells

Myeloid cells that play a major role in the initiation of T cell-dependent immune responses.

Myeloid-derived suppressor cells

(MDSCs). A heterogeneous population of cells that are defined by their myeloid origin, immature state and ability to potently suppress T cell responses.

Integrated stress response

Evolutionarily conserved homeostatic programme common to all eukaryotic cells.

Mitokines

Soluble factors released by cells experiencing mitochondrial stress and operating as autocrine, paracrine or endocrine mediators.

AMP-activated protein kinase

(AMPK). Phylogenetically conserved enzyme expressed by all mammalian cells that has a major role in the regulation of energy metabolism.

Mitochondrial outer membrane permeabilization

(MOMP). Loss of integrity of the outer mitochondrial membrane that generally precipitates regulated cell death through apoptosis.

Inflammasome

Supramolecular complex responsible for the caspase 1-dependent maturation of IL-1β and IL-18 in response to microbial products or other danger signals.

γδ T lymphocytes

T cells expressing a γδ (rather than an αβ) T cell receptor, which is associated with a fairly limited antigenic repertoire but major histocompatibility complex-independent recognition.

Cancer-associated fibroblasts

Fibroblasts that are found in the tumour microenvironment and generally support malignant cells by nutritional and immunological mechanisms.

Ketone bodies

Three related compounds (acetone, acetoacetic acid and β-hydroxybutyric acid) that are produced during the metabolism of lipids.

Stellate cells

Hepatic or pancreatic cells that have a major role in the establishment and maintenance of fibrosis.

Pro-opiomelanocortin neurons

Hypothalamic neurons capable of synthesizing pro-opiomelanocortin (POMC), the precursor of circulating melanocyte stimulating hormone, adrenocorticotropin hormone and β-endorphin

Non-conventional secretion

Process through which intracellular proteins and other cytoplasmic components are released into the extracellular milieu independently of the endoplasmic reticulum and Golgi apparatus.

Paneth cells

Cells from the intestinal epithelium that contribute to the maintenance of the gastrointestinal barrier.

Crohn’s disease

Chronic inflammatory condition of the gastrointestinal tract associated with an increased risk of colorectal cancer.

Exosomes

Cell-derived small vesicles that are present in virtually all mammalian fluids, including blood and urine.

Senolytic drugs

Agents that selectively kill senescent cells.

Programmed cell death

(PCD). Purely physiological variant of regulated cell death that contributes to post-embryonic or embryonic development as well as to the maintenance of adult tissue homeostasis.

Systemic lupus erythematosus

(SLE). Mild to severe autoimmune disease affecting a variety of tissues, including joints, skin, heart and lungs.

LC3-associated phagocytosis

Specific variant of the phagocytic process that relies on multiple, but not all, components of the molecular apparatus for autophagy.

Damage-associated molecular patterns

(DAMPs). Endogenous molecules that, upon exposure on the plasma membrane or secretion, can be recognized by a pattern recognition receptor and hence participate in the regulation of inflammatory responses.

Pyroptosis

Variant of regulated cell death that is associated with the formation of pores in the plasma membrane by one of multiple gasdermin family members.

RIGI-like receptors

(RLRs). Intracellular pattern recognition receptors involved in the recognition of nucleic acids (generally, but not exclusively, of viral origin).

Necroptosis

Variant of regulated cell death that involves RIPK3-dependent activation of MLKL, resulting in plasma membrane permeabilization.

Immunogenic cell death

(ICD). Functionally defined variant of regulated cell death that is sufficient (in immunocompetent hosts) to establish protective immune responses specific for antigens from dying cells.

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Galluzzi, L., Yamazaki, T. & Kroemer, G. Linking cellular stress responses to systemic homeostasis. Nat Rev Mol Cell Biol 19, 731–745 (2018). https://doi.org/10.1038/s41580-018-0068-0

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