Live to die another way: modes of programmed cell death and the signals emanating from dying cells

Key Points

  • During development, programmed cell death has various functions, including sculpting and deletion of structures, supply of nutrients, regulation of cell number and elimination of abnormal and dangerous cells.

  • Several distinct mechanisms of programmed cell death are used to eliminate cells; we discuss the biological significance of these pathways in vivo.

  • Caspase activation is subjected to many layers of coordinated upstream regulation, which ensure that the cell is killed only after several checkpoints have been cleared.

  • Is autophagy a cell death mechanism? Here, we carefully review the data that support autophagy as a bona fide mechanism of cell destruction.

  • For many years, necrosis was regarded as an unregulated mode of cell death that was caused by overwhelming trauma. Here, we examine a regulated form of necrosis termed necroptosis.

  • Traditionally, it was thought that dying cells have limited effects on the cellular environment. However, it is now clear that apoptotic cells release signals that can trigger tissue regeneration.

  • Cells that are undergoing apoptosis can instruct additional killing in their cellular environment, which explains how 'communal suicide' can occur.


All life ends in death, but perhaps one of life's grander ironies is that it also depends on death. Cell-intrinsic suicide pathways, termed programmed cell death (PCD), are crucial for animal development, tissue homeostasis and pathogenesis. Originally, PCD was almost synonymous with apoptosis; recently, however, alternative mechanisms of PCD have been reported. Here, we provide an overview of several distinct PCD mechanisms, namely apoptosis, autophagy and necroptosis. In addition, we discuss the complex signals that emanate from dying cells, which can either trigger regeneration or instruct additional killing. Further advances in understanding the physiological roles of the various mechanisms of cell death and their associated signals will be important to selectively manipulate PCD for therapeutic purposes.

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Figure 1: The core of the apoptotic machinery is conserved.
Figure 2: Crosstalk between autophagy-related and apoptosis-related proteins.
Figure 3: Tumour necrosis factor-mediated survival, apoptosis and necroptosis.
Figure 4: Apoptosis-induced proliferation.
Figure 5: Apoptosis-induced apoptosis.


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The authors thank Y. Fox for help with the figures and F. Kol for ongoing support. H.S. is an investigator with the Howard Hughes Medical Institute and is supported by the US National Institutes of Health grant RO1GM60124. Y.F. is supported by the Deloro Career Advancement Chair and the Alon Fellowship.

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Correspondence to Yaron Fuchs or Hermann Steller.

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Initiator caspases

Caspases that cleave inactive forms of executioner caspases.

Executioner caspases

Caspases that cleave various cellular proteins, often leading to apoptosis.


A protein platform that is formed during apoptosis. This platform comprises cytochrome c that has translocated from the mitochondria to the cytoplasm and apoptotic protease- activating factor 1 (APAF1).

Mitochondrial outer membrane permeabilization

(MOMP). An event regulated by the BCL-2 protein family that is considered to be the 'point of no return' at which the cell commits to apoptosis.

Death-inducing signalling complex

(DISC). A protein platform formed by death receptors that can drive apoptosis.

Baculovirus IAP repeat domain

(BIR domain). A domain present in inhibitor of apoptosis proteins (IAPs) that can bind to caspases as well as to pro-apoptotic factors such as IAP antagonists.

Hair follicle stem cells

(HFSCs). Adult stem cells that are normally situated in a niche called the bulge and that function to replenish the hair follicle.

Linker cell

A migratory cell of the Caenorhabditis elegans male gonad that dies in a non-apoptotic, caspase- independent manner.

Autophagic cell death

A reported mode of programmed cell death that is associated with the presence of autophagosomes and that depends on autophagy-related proteins.

Necrostatin 1

A potent and selective inhibitor of necroptosis that was originally reported as a selective allosteric inhibitor of the death domain receptor-associated adaptor kinase RIP1 in the necroptosis pathway.

Damage-associated molecular patterns

(DAMPs; also known as alarmins). Molecules that are released by stressed cells and that function as endogenous danger signals to initiate and propagate the inflammatory response.

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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).

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