Self-consumption: the interplay of autophagy and apoptosis

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Abstract

Autophagy and apoptosis control the turnover of organelles and proteins within cells, and of cells within organisms, respectively, and many stress pathways sequentially elicit autophagy, and apoptosis within the same cell. Generally autophagy blocks the induction of apoptosis, and apoptosis-associated caspase activation shuts off the autophagic process. However, in special cases, autophagy or autophagy-relevant proteins may help to induce apoptosis or necrosis, and autophagy has been shown to degrade the cytoplasm excessively, leading to 'autophagic cell death'. The dialogue between autophagy and cell death pathways influences the normal clearance of dying cells, as well as immune recognition of dead cell antigens. Therefore, the disruption of the relationship between autophagy and apoptosis has important pathophysiological consequences.

Key Points

  • Autophagy and apoptosis constitute functionally distinct mechanisms for the turnover or destruction of cytoplasmic structures within cells and of cells within organisms, respectively.

  • Multiple stress-elicited signal transduction pathways can sequentially induce autophagy and apoptosis within the same cell. Elements of such pathways include p53, BH3 (BCL-2 homology 3)-only proteins, several kinases (including AKT, DAPK (death-associated protein kinase) and JNK (JUN N-terminal kinase)) and oncoproteins such as MYC and RAS.

  • Autophagy increases the threshold of stress required for the induction of cell death by several mechanisms. These include the selective removal of damaged, potentially apoptosis-inducing mitochondria or that of other potentially lethal organelles, such as damaged zymogen granules in the exocrine pancreas. Autophagy can also lead to the selective elimination of pro-apoptotic signal transducers.

  • Apoptosis-associated caspase activation leads to the cleavage of various essential pro-autophagic proteins. Several of the resulting fragments acquire a new, pro-apoptotic function. This mechanism may accelerate the apoptotic demise of cells at its final stage.

  • Cell death frequently occurs with (or is preceded by) autophagy, but it is rarely truly mediated by autophagy. In some cases, autophagic membranes or individual autophagy-relevant proteins facilitate the activation of apoptotic or necrotic pathways. There are also a few examples in which autophagy may be responsible for lethally dismantling cells. This cell death by autophagy is referred to as autophagic cell death (ACD).

  • Soluble products released by dying or dead cells can induce autophagy in neighbouring cells via the activation of pattern recognition receptors (PRRs). Pre-mortem autophagy is important for the production of chemotactic signals, which determine the removal of dead cells, inflammatory reactions and immune responses against dead-cell antigens.

  • Crosstalk between autophagy and apoptosis, as it occurs within the same cell or between distinct cells, has a cardinal role in pathophysiological processes, including those related to cancer, hormesis and ageing.

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Figure 1: Signals that induce both apoptosis and autophagy.
Figure 2: Effects of autophagy on lethal signalling.
Figure 3: Impact of autophagy on the removal of dead cells in tissues.
Figure 4: Functional relationship between autophagy and apoptosis.

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Acknowledgements

The authors are supported by the Ligue contre le Cancer (équipe labellisée), Agence National de la Recherche, AXA Chair for Longevity Research, Association pour la Recherche sur le Cancer, Cancéropôle Ile-de-France, Institut National du Cancer (INCa), Fondation Bettencourt-Schueller, Fondation de France, Fondation pour la Recherche Médicale, the European Commission (ArtForce), the European Research Council, the LabEx Immuno-Oncology, the SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (Socrate), Cancer Research and Personalized Medicine (Carpem), the Paris Alliance of Cancer Research Institutes, the National Institutes of Health and the Ellison Medical Foundation.

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Correspondence to Guido Kroemer.

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The authors declare no competing financial interests.

Supplementary information

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Contribution of individual components of the Beclin 1 interactome to autophagy and apoptosis. (PDF 121 kb)

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Glossary

Autophagosomes

Vesicles characterized by two membranes that contain autophagic cargo.

Autolysosomes

Fusion proteins of autophagosomes and lysosomes, also called autophagolysosomes. Autolysosomes only have one membrane.

Programmed cell death

(PCD). Cell death that occurs during development or adult tissue homeostasis for the removal of superfluous cells.

Mitochondrial outer membrane permeabilization

(MOMP). An apoptosis-associated process that results in the release of apoptosis-inducing proteins (such as cytochrome c, AIF (apoptosis-inducing factor), SMAC (second mitochondria-derived activator of caspase) and others) that are normally retained in the mitochondrial intermembrane space, through the outer membrane into the cytosol.

Caspases

A family of Cys proteases that cleave after Asp residues. Initiator caspases are typically activated in response to a particular triggering event (for example, caspase 8 upon death receptor ligation, caspase 9 upon apoptosome activation and caspase 2 upon DNA damage), whereas effector caspases (mainly caspase 3, caspase 6 and caspase 7) are particularly important for the ordered dismantling of vital cellular structures.

p53

A central tumour suppressor protein that has multiple functions, both in the cytoplasm and in the nucleus. As a transcription factor, p53 transactivates genes that induce cell cycle arrest, cellular senescence, autophagy and apoptosis.

Lysosomal membrane permeabilization

(LMP). A disruption of lysosomal membrane function that leads to the translocation of lysosomal hydrolases, including cathepsins, from the lysosomal lumen to the rest of the cell. LMP can be induced by endogenous signal transducers (such as reactive oxygen species and sphingosine), as well as by lysosomotropic drugs.

BCL-2 family

Each member of this protein family contains at least one BCL-2 homology (BH) region. The family is divided into anti-apoptotic multidomain proteins (such as BCL-2, BCL-XL (BCL extra large) and MCL1 (myeloid cell leukaemia sequence 1)), which contain four BH domains (BH1, BH2, BH3 and BH4), pro-apoptotic multidomain proteins (for example, BAX (BCL-2- associated X protein) and BAK (BCL-2 antagonist or killer)), which contain BH1, BH2 and BH3, and the pro-apoptotic BH3-only protein family.

Unfolded protein response

(UPR). The UPR is activated in response to stress in the endoplasmic reticulum (ER). It enables cells to adapt to ER stress by reducing the quantity of misfolded proteins in this organelle.

Senescence

An irreversible G1 cell cycle arrest that is accompanied by morphological changes (flattening of the cells), metabolic alterations and transcriptional reprogramming that leads to the expression of cell cycle blockers, such as p16 and p21, and senescence-associated ß-galactosidase.

Cytochrome c

A haem protein exclusively present in the mitochondrial intermembrane space. During the initiation of apoptosis, cytochrome c is released from mitochondria and triggers the assembly of the apoptosome, which is a caspase activation complex.

Reactive oxygen species

(ROS). Classic oxygen radicals and peroxides that are formed within cells.

Death receptors

Cell surface receptors that activate the extrinsic pathway of apoptosis upon ligand-induced trimerization. The family of death receptors includes CD95 (which binds CD95 ligand), tumour necrosis factor receptor 1 (TNFR1) and two receptors for TNF-related apoptosis-inducing ligand (TRAILR1 and TRAILR2).

Sphingosine kinase

A conserved lipid kinase that catalyses the formation of the bioactive sphingolipid metabolite sphingosine 1- phosphate. This acts as a second messenger, with important roles in numerous physiological processes, including cell growth, motility and survival.

Danger-associated molecular patterns

(DAMPs). These molecules are released by or exposed on the surface of stressed and dying cells. They initiate and perpetuate sterile inflammatory responses.

Pattern recognition receptors

(PRRs). A series of intracellular or surface receptors that sense danger-associated molecular patterns (DAMPs) or foreign structures from infectious pathogens, triggering inflammatory and immune responses.

Heterophagy

Phagocytosis of a cell by another cell. Heterophagy has a major role in the efficient removal of apoptotic cells. Efficient heterophagy is indispensable for avoiding inflammatory responses triggered by apoptotic material.

Amyotrophic lateral sclerosis

(ALS). A progressive and debilitating neurodegenerative disease that is characterized by progressive muscle atrophy and other degenerative manifestations. The disease pathophysiology is complex and not yet fully understood, but it is proposed to involve the accumulation of misfolded proteins.

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