Disassembly of the Dying: Mechanisms and Functions

doi:10.1016/j.tcb.2016.08.011

Trends in Cell Biology

Volume 27, Issue 2, February 2017, Pages 151-162

https://doi.org/10.1016/j.tcb.2016.08.011 Get rights and content

Trends

Apoptotic cell disassembly is a highly complex process regulated by a series of well-coordinated morphological steps including apoptotic membrane blebbing, apoptotic protrusion formation, and fragmentation.

Plasma-membrane blebbing is not the sole process required for apoptotic body (ApoBD) formation, but membrane protrusions including microtubule spikes, apoptopodia, and beaded apoptopodia may act in concert to aid the generation of ApoBDs.

The mechanism of how apoptotic cells disassembly can determine the quantity and quality (size and contents) of ApoBDs.

ApoBDs can aid intercellular communication by transporting DNA, microRNAs, proteins, and infectious agents between cells.

Several clinically approved drugs can target the apoptotic cell disassembly process and may represent novel therapeutics to treat diseases associated with cell death.

The disassembly of an apoptotic cell into subcellular fragments, termed apoptotic bodies (ApoBDs), is a hallmark of apoptosis. Although the generation of ApoBDs is generally understood as being stochastic, it is becoming increasingly clear that ApoBD formation is a highly regulated process involving distinct morphological steps and molecular factors. Functionally, ApoBDs could facilitate the efficient clearance of apoptotic material by surrounding phagocytes as well as mediate the transfer of biomolecules including microRNAs and proteins between cells to aid in intercellular communications. Therefore, the formation of ApoBDs is an important process downstream from apoptotic cell death. We discuss here the mechanisms and functions of apoptotic cell disassembly.

Section snippets

Cell Disassembly as a Key Downstream Process of Apoptotic Cell Death

Billions of cells undergo apoptosis (a form of programmed cell death) daily as part of physiological homeostasis [1]. At later stages of apoptosis, some cell types can generate subcellular (1–5 μm) membrane-bound extracellular vesicles termed apoptotic bodies (ApoBDs, see Glossary) 1, 2, 3. ApoBDs are the largest type of extracellular vesicle compared to microparticles (50–1000 nm) and exosomes (30–100 nm) 2, 4, 5, 6 (Box 1). The formation of ApoBDs involves a series of morphological changes

Molecular Mechanisms of Apoptotic Cell Disassembly

The dismantling of an apoptotic cell into ApoBDs has been thought to be a stochastic process. However, recent studies suggest that the generation of ApoBDs is controlled by several well-coordinated morphological steps. The apoptotic cell disassembly process can be divided into three sequential steps governed by distinct morphological changes [1] (Figure 1). Step 1 describes the formation of plasma-membrane blebs on the cell surface. Particular cell types can then generate thin membrane

The Role of Apoptotic Cell Disassembly in Cell Clearance and Intercellular Communication

The formation of ApoBDs has been proposed to mediate two key functions: (i) to aid in the efficient removal of apoptotic cells, and (ii) to carry biomolecules such as nucleic acids and proteins to facilitate intercellular communication. We describe here the functions of apoptotic cell disassembly and the importance of this process in normal physiological and pathological conditions.

Concluding Remarks and Future Directions

It is becoming increasingly clear that apoptotic cell disassembly is a complex process, involving highly coordinated morphological steps. Depending on the mechanism used by a particular cell type to undergo apoptotic cell disassembly, a different quantity and quality of ApoBDs will be generated. These observations raise several unanswered questions as to why different cell types need to disassemble differently and the functional significance of such diversity (see Outstanding Questions).

Acknowledgments

We like to thank members of the laboratories of Mark Hulett and I.K.H.P. for discussions. This work was supported by Australian Postgraduate Awards to G.K.A-S and the La Trobe University Nicholas Hoogenraad Fellowship to I.K.H.P.

Glossary

Actomyosin contraction: a cellular process that describes the generation of contractile force though the interaction between filamentous actin and myosin II.
Apoptotic body (ApoBD): a subcellular (1–5 μm diameter) extracellular vesicle generated from an apoptotic cell at the final stages of apoptotic cell disassembly.
Apoptotic cell: a cell that has begun apoptosis but has not undergone apoptotic cell disassembly.
Apoptopodia: string-like membrane protrusions found on apoptotic cells.
Beaded apoptopodia

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Trends in Cell Biology

ReviewDisassembly of the Dying: Mechanisms and Functions

Trends

Section snippets

Cell Disassembly as a Key Downstream Process of Apoptotic Cell Death

Molecular Mechanisms of Apoptotic Cell Disassembly

The Role of Apoptotic Cell Disassembly in Cell Clearance and Intercellular Communication

Concluding Remarks and Future Directions

Acknowledgments

Glossary

Exp. Cell Res.

Blood

Curr. Opin. Cell Biol.

J. Biol. Chem.

Immunity

J. Proteomics

Semin. Hematol.

Curr. Biol.

J. Lipid Res.

Lab. Invest.

Immunopharmacology

J. Invest. Dermatol.

J. Biol. Chem.

Cell Rep.

Exp. Cell Res.

Virology

A novel mechanism of generating extracellular vesicles during apoptosis via a beads-on-a-string membrane structure

Nat. Commun.

Biogenesis of extracellular vesicles (EV): exosomes, microvesicles, retrovirus-like vesicles, and apoptotic bodies

J. Neurooncol.

Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics

Br. J. Cancer

Cellular mechanisms underlying the formation of circulating microparticles

Arterioscler. Thromb. Vasc. Biol.

Microparticles in cardiovascular diseases

Cardiovasc. Res.

Exosomes: composition, biogenesis and function

Nat. Rev. Immunol.

Apoptotic membrane blebbing is regulated by myosin light chain phosphorylation

J. Cell Biol.

A novel role for microtubules in apoptotic chromatin dynamics and cellular fragmentation

J. Cell Sci.

Unexpected link between an antibiotic, pannexin channels and apoptosis

Nature

Apoptotic cell clearance: basic biology and therapeutic potential

Nat. Rev. Immunol.

The role of defective clearance of apoptotic cells in systemic autoimmunity

Nat. Rev. Rheumatol.

Delivery of microRNA-126 by apoptotic bodies induces CXCL12-dependent vascular protection

Sci. Signal.

Radiation-induced formation of apoptotic bodies in rat thymus

Radiat. Res.

Niche-induced cell death and epithelial phagocytosis regulate hair follicle stem cell pool

Nature

Phosphatidylserine receptor BAI1 and apoptotic cells as new promoters of myoblast fusion

Nature

Non-equilibration of hydrostatic pressure in blebbing cells

Nature

Caspase-3-mediated cleavage of ROCK I induces MLC phosphorylation and apoptotic membrane blebbing

Nat. Cell Biol.

Apoptotic and necrotic blebs in epithelial cells display similar neck diameters but different kinase dependency

Cell Death Differ.

Membrane blebbing during apoptosis results from caspase-mediated activation of ROCK I

Nat. Cell Biol.

Blebs produced by actin-myosin contraction during apoptosis release damage-associated molecular pattern proteins before secondary necrosis occurs

Cell Death Differ.

Matrix-bound PAI-1 supports cell blebbing via RhoA/ROCK1 signaling

PLoS One

Caspase-mediated cleavage and activation of LIM-kinase 1 and its role in apoptotic membrane blebbing

Genes Cells

Cofilin phosphorylation by LIM-kinase 1 and its role in Rac-mediated actin reorganization

Nature

Regulation of actin dynamics through phosphorylation of cofilin by LIM-kinase

Nature

Membrane and morphological changes in apoptotic cells regulated by caspase-mediated activation of PAK2

Science

Review
Disassembly of the Dying: Mechanisms and Functions