The molecular relationships between apoptosis, autophagy and necroptosis

doi:10.1016/j.semcdb.2015.02.003

Seminars in Cell & Developmental Biology

Volume 39, March 2015, Pages 63-69

https://doi.org/10.1016/j.semcdb.2015.02.003 Get rights and content

Abstract

Cells are constantly subjected to a vast range of potentially lethal insults, which may activate specific molecular pathways that have evolved to kill the cell. Cell death pathways are defined partly by their morphology, and more specifically by the molecules that regulate and enact them. As these pathways become more thoroughly characterized, interesting molecular links between them have emerged, some still controversial and others hinting at the physiological and pathophysiological roles these death pathways play. We describe specific molecular programs controlling cell death, with a focus on some of the distinct features of the pathways and the molecular links between them.

Graphical abstract

Section snippets

“Intrinsic” or “Bcl-2 regulatable” apoptosis

The intrinsic apoptotic pathway contributes to normal embryonic development and the homeostasis of cell number in all multicellular organisms. When the intrinsic cell death pathway is inactivated, for example in gene-deletion mouse models, abnormally increased cell numbers accumulate in various organs. This has been observed in the developing nervous system when two critical genes called BAX and BAK are deleted and in the hematopoietic compartment when another gene, BIM, is inactivated [1], [2]

Autophagy

More recently, there has been interest in the role autophagy may play in cell death, and how this may intersect with the intrinsic cell death pathway. Autophagy is a cellular mechanism of “self-eating”, in which proteins and organelles are encased in specialized intracellular vesicles and are then broken down by lysosomal proteases for recycling. A basal or low level of autophagy occurs in most cells at resting state. During times of stress, such as nutrient starvation or treatment with certain

Autophagy and cell death

Sometimes referred to as Type II cell death, autophagic cell death has had a confusing history. In some instances, autophagic cell death has been identified principally by the presence of autophagosomes or increased rates of autophagy only, while others have a stricter definition and include a functional outcome – cell death must be directly due to autophagy. The latter seems most informative and the general trend in the field seems to be shifting in this direction. The Nomenclature Committee

Extrinsic cell death pathways

In many immune cells, and particularly in lymphocytes, cell death can be triggered by the specific engagement of a subset of the TNF Receptor family by their ligands. The most well characterized ligands of these receptors to date are FasL and TNF-α. This form of cell death plays a critical role in the deletion of autoreactive immune cells to limit inflammatory responses. When this pathway is inactivated by naturally occurring mutations or by gene deletion, autoimmune disease is a consequence

Necroptosis: a programmed necrosis

Necrotic death is generally a result of an over-whelming cytotoxic insult, and requires no specific molecular events in order for it to occur. However, in the last decade, a regulated form of necrotic cell death has been characterized and termed necroptosis, because it shares features of apoptosis and necrosis. Like apoptosis, a defined molecular cascade controls necroptosis. Like necrosis, necroptosis is characterized by swelling of the cell and its organelles leading to cell rupture. Rupture

Autophagy and necroptosis together?

Currently, it is less clear how potential interactions between autophagy and necroptosis pathways fit into the increasingly complex network of the different ways in which cells can die. Nevertheless, there are data that point to such interactions. In studies of murine fibroblast L929 cells, cell death was initiated solely by the treatment with a pan-caspase inhibitor zVAD [45]. This death response was in part characterized by the development of autophagosomic vacuoles. Because reducing RIPK1,

Conclusion

The same deleterious insult can engage different, molecularly distinct routes to cell death. There are also several points at which these pathways converge on shared molecules and, in many cases, these are regulatory points at which cells may “decide” the manner of their death. Whilst it is evident that certain cellular stresses always engage a particular cell death pathways such as the BCL-2 regulatable pathway, it is also clear that other cytotoxic responses, such as cytotoxic lymphocyte

Acknowledgements

LML holds a Peter Doherty Early Career Fellowship from the NHMRC (1035502). This work was made possible through Victorian State Government Operational Infrastructure Support and Australian Government NHMRC IRIISS (#361646).

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¹: All authors have contributed equally to this review.

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ReviewThe molecular relationships between apoptosis, autophagy and necroptosis

Abstract

Graphical abstract

Section snippets

“Intrinsic” or “Bcl-2 regulatable” apoptosis

Autophagy

Autophagy and cell death

Extrinsic cell death pathways

Necroptosis: a programmed necrosis

Autophagy and necroptosis together?

Conclusion

Acknowledgements

Cell

Cell

Biochim Biophys Acta

Cell

Cell

Cell

Mol Cell

Cell

Cell

Exp Cell Res

J Biol Chem

J Biol Chem

Cell

Cell

Curr Biol

Mol Cell

Cell

Cell

Curr Opin Immunol

Mol Cell

Mol Cell

Cell

Immunity

Cell

Cell

Cancer Lett

J Biol Chem

J Biol Chem

Free Radic Biol Med

Cell Host Microbe

Curr Biol

Immunity

Cell

Cell

Cell Rep

Immunity

Mol Cell

Cell

Cell Host Microbe

Cell Rep

Cell

Proapoptotic Bcl-2 relative Bim required for certain apoptotic responses, leukocyte homeostasis, and to preclude autoimmunity

Science

Cell death in the absence of Bax and Bak

Cell Death Differ

Involvement of the bcl-2 gene in human follicular lymphoma

Science

Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells

Nature

The role of BH3-only proteins in the immune system

Nat Rev Immunol

Apoptotic pore formation is associated with in-plane insertion of Bak or Bax central helices into the mitochondrial outer membrane

Proc Natl Acad Sci U S A

Control of apoptosis by the BCL-2 protein family: implications for physiology and therapy

Nat Rev Mol Cell Biol

The release of cytochrome c from mitochondria – a primary site for bcl-2 regulation of apoptosis

Science

Molecular characterization of mitochondrial apoptosis-inducing factor

Nature

Review
The molecular relationships between apoptosis, autophagy and necroptosis