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Four deaths and a funeral: from caspases to alternative mechanisms

Key Points

  • Classic apoptosis is characterized by a stereotyped series of morphological changes, including chromatin condensation and rapid uptake of the corpses by neighbouring cells. Since many forms of programmed cell death (PCDs), including autophagy, paraptosis, dark cell death and 'necrosis-like PCD' result in a non-apoptotic morphology, the biochemical pathways of PCD might be far more diverse than first predicted. Other proteases are proposed to take over the role of caspases for cleaving for example nuclear lamins and cytoskeletal elements.

  • There are many distinct forms of non-apoptotic PCD. In 'apoptosis-like PCD', chromatin may condense, but not to the characteristic geometric shape associated with classic apoptosis; in 'necrosis-like PCD' chromatin may not condense at all. All of them may be mediated by classic death receptors and result in the display of 'eat-me' signals.

  • The classic role of caspases in promoting PCD is now being refined as more cases are found in which caspases are shown to control the morphology of cell death rather than the actual decision to die. In other examples of PCD they are not required at all. This has led to the proposal that other evolutionary ancient and conserved pathways exist.

  • Mitochondria can trigger cell death by activation of different pathways, which may be caspase-dependent or independent. Although these pathways may be triggered simultaneously, the final outcome and form of cell death will depend on the individual cell type, the initial triggers, and the metabolic situation.

  • The control of apoptosis is often misregulated in tumours and, although many cancer therapies induce classic apoptosis, potential drugs that engage other PCD routes are emerging.

  • In the adult nervous system, it is crucial that the induction of PCD is tightly controlled to prevent unnecessary damage. For this reason, there seem to be additional layers of control for caspase activation. For instance, cells might first require a 'competence to die' signal before apoptosis can be subsequently activated, and often caspase-independent death pathways are preferentially activated.

Abstract

A single family of proteases, the caspases, has long been considered the pivotal executioner of all programmed cell death. However, recent findings of evolutionarily conserved, caspase-independent controlled death mechanisms have opened new perspectives on the biology of cell demise, with particular implications for neurobiology, cancer research and immunological processes.

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Figure 1: Multiple death pathways triggered by death receptors.
Figure 2: Mitochondrial roles in caspase-independent PCD.
Figure 3: Alternative death pathways as regulators of tumour cell survival and as putative targets for cancer therapy.
Figure 4: Different modes of neuronal death.

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Acknowledgements

We acknowledge our colleagues for stimulating discussions and the Danish Cancer Society, the German Research Council and the Danish Medical Research Council for financial support. We also apologize to those whose work could only be cited indirectly.

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Movie 1

Time lapse imaging of blebbing process in caspase-independent death. WEHI-S murine fibrosarcoma cells were recorded by time lapse videomicroscopy with Varel contrast optics; all sequences correspond to about 1 h in real time. Nuclear morphology was recorded in parallel after staining with H-33342 (not shown; see Ref. 9). Exposure to tumour necrosis factor and activation of caspases. Intensive zeiosis (average active blebbing time per cell = 20 min). Formation of a terminal bleb marks cell death (energy failure) associated with chromatin condensation.

Please note that this movie may take a few seconds to download.

Movie 2

Time lapse imaging of blebbing process in caspase-independent death. WEHI-S murine fibrosarcoma cells were recorded by time lapse videomicroscopy with Varel contrast optics; all sequences correspond to about 1 h in real time. Nuclear morphology was recorded in parallel after staining with H-33342 (not shown; see Ref. 9). Exposure to tumour necrosis factor in the presence of the caspase-inhibitor zVADfmk. Intensive zeiosis (average active blebbing time per cell = 20 min). Formation of a terminal bleb marks cell death (energy failure) associated with chromatin condensation.

Please note that this movie may take a few seconds to download.

Movie 3

Time lapse imaging of blebbing process in caspase-independent death. WEHI-S murine fibrosarcoma cells were recorded by time lapse videomicroscopy with Varel contrast optics; all sequences correspond to about 1 h in real time. Nuclear morphology was recorded in parallel after staining with H-33342 (not shown; see Ref. 9). Simple cell lysis (necrosis) triggered by 2-mM chloroquine. No change in nuclear morphology, no zeiosis.

Please note that this a large (3MB) movie which may take a while to download.

Movie 4

Time lapse imaging of blebbing process in caspase-independent death. WEHI-S murine fibrosarcoma cells were recorded by time lapse videomicroscopy with Varel contrast optics; all sequences correspond to about 1 h in real time. Nuclear morphology was recorded in parallel after staining with H-33342 (not shown; see Ref. 9). Oligomycin-induced passive formation of a simple terminal bleb (energy failure) in the absence of zeiosis and cell movement. No change in nuclear morphology.

Please note that this movie may take a few seconds to download.

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DATABASE LINKS

Bax

CED-9

Bcl-2

CED-3

poly(ADP) ribose polymerase

CD2

TNF

p21-activated kinase-2

cathepsin D

cathepsin B

TNFR1

Fas

FADD

Daxx

ASK1

JNK1

Hsp27

Bak

Bid

Bim

Bcl-xL

DIABLO/Smac

AIF

CAD

ORP150

Myc

E2F

CDC25

survivin

p53

p19arf

PML

RARα

CD47

Bin1

APP

ataxins

presenilins

huntingtin

tau

α-synuclein

PTEN

FURTHER INFORMATION

Cell Death Society

Jäättelä lab

Glossary

CASPASES

Family of cysteine proteases that can be divided into inflammatory caspases, and pro-apoptotic caspases, which can be further grouped into initiator and effector caspases.

PHAGOCYTOSIS

Uptake of dying cells by macrophages or neighbouring cells. Recognition of 'eat-me' signals by specific receptors on the phagocytosing cell.

DEATH RECEPTORS

A family of cell-surface receptors that can mediate cell death upon ligand-induced trimerization.

OEDEMA

Water accumulation and swelling within a tissue, cell or organelle.

ZEIOSIS

Dynamic plasma membrane blebbing of a dying cell, analogous to the bubbling of fermenting yeast.

PHOSPHATIDYLSERINE EXPOSURE

Translocation of phosphatidylserine, which is confined to the inner leaflet of the plasma membrane in healthy cells, to the outside of the plasma membrane where it is recognized by a specific receptor on macrophages.

PARAPTOSIS

A form of programmed cell death without prominent chromatin condensation and mainly characterized by cytoplasmic vacuolization.

MALE LINKER CELL

The linker cell is a male-specific cell at the tip of the developing gonad. It 'guides' growth of the male gonad from the midbody region towards the tail. When the gonad has reached the tail late in larval development, the linker cell is 'murdered' by one of two neighbouring cells.

DARK CELL DEATH

Slow neuronal death observed, for example, during Huntington's disease. Characterized by strong cytoplasmic condensation, chromatin clumping, ruffling of the cell membrane, but no blebbing of the nucleus or plasma membrane.

PARP

Poly(ADP)-ribose polymerase. A nuclear enzyme activated by DNA damage and reducing cellular ATP levels when overactivated.

STAUROSPORINE

Plant-derived cytotoxin known to trigger mitochondria-dependent apoptosis in most cell types. Model apoptosis inducer.

COLCHICINE

A microtubule-depolymerizing poison. Leads to loss of neurites in neurons and to apoptosis in most cell types.

PAN-CASPASE INHIBITORS

Cell-permeable irreversible inhibitors of all caspases examined so far that block or retard caspase-dependent processes. Widely used examples include z-Val-Ala-Asp-fluoromethylkethone (z-VAD-fmk) and Boc-Asp-fluoromethylketone.

INHIBITOR OF APOPTOSIS PROTEIN

(IAP). A class of proteins (IAP, XIAP, NAIP) containing a BIR domain that can act as an intracellular caspase inhibitor.

DEATH DOMAIN

A conserved sequence motif first identified in the intracellular parts of death receptors. Later recognized as the key motif for association of the receptors with cytosolic death-domain-containing proteins (FADD, TRADD, RIP) and the induction of cell death.

REACTIVE OXYGEN SPECIES

(ROS). Collective term comprising intracellularly formed classic oxygen radicals and peroxides.

APOPTOSOME

Multiprotein complex containing cytochrome c, Apaf-1 and procaspase-9. Catalyses ATP-dependent auto-activation of caspases by induced proximity. Key regulatory step of developmental apoptosis.

AIF

Apoptosis-inducing factor, a flavoprotein normally located in the mitochondrial intermembrane space. It is released during apoptosis and is involved in nuclear changes and death induction.

ONCOPROTEINS

Oncoproteins are encoded by oncogenes and their increased activity or expression promotes tumorigenesis either by inducing proliferation or by inhibiting cell death.

PTEN

A tumour-suppressor protein with phosphatase activity specific for inositol phospholipids. Negative regulator of protein kinase B (Akt) pathway in cells.

PYKNOSIS

Poorly defined pathological term for nuclear condensation. Mainly used to describe forms of non-apoptotic chromatin condensation.

EXCITOTOXICITY

Neuronal death triggered by overexcitation of ion channel-gating (ionotropic) receptors (for example, ionotropic glutamate receptors). Release of endogenous excitotoxins triggers excitotoxic processes as common mechanism of neuronal loss during cerebral ischaemia.

HORIZONTAL TRANSFER

Non-germline transmission of genetic material.

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Leist, M., Jäättelä, M. Four deaths and a funeral: from caspases to alternative mechanisms. Nat Rev Mol Cell Biol 2, 589–598 (2001). https://doi.org/10.1038/35085008

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