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Another Way to Die: Autophagic Programmed Cell Death

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Another Way to Die: Autophagic Programmed Cell Death Cell Death and Differentiation (2005) 12, 1528–1534 & 2005 Nature Publishing Group All rights reserved 1350-9047/05 $30.00 www.nature.com/cdd Review Another way to die: autophagic programmed cell death Y Tsujimoto*,1,2 and S Shimizu1,2 process that is associated with autophagosomes and auto- lysosomes. 1 Laboratory of Molecular Genetics, Department of Medical Genetics, Osaka University Medical School, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan 2 SORST of Japan Science Technology Corp., 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan Autophagy * Corresponding author: Y Tsujimoto, Laboratory of Molecular Genetics, Department of Medical Genetics, Osaka University Medical School, 2-2 Here, we briefly summarize the well-established process Yamadaoka, Suita, Osaka 565-0871 Japan. Tel: þ 81-6-6879-3360; of autophagosome formation. Readers who are interested Fax: þ 81-6-6879-3369; E-mail: [email protected] in more detailed information on autophagy should refer to several excellent recent reviews.2–4 Received 06.5.05; revised 18.8.05; accepted 18.8.05 Edited by G Melino Autophagosomes are double-membrane cytoplasmic vesi- cles that are designed to engulf various cellular constituents, including cytoplasmic organelles (Figure 1). Autophago- Abstract somes fuse to lysosomes to become autolysosomes, where sequestered cellular components are digested. Autophago- Programmed cell death (PCD) is one of the important terminal somes and autolysosomes are formed during a process called paths for the cells of metazoans, and is involved in a variety of macroautophagy (hereafter this is referred to as ‘autophagy’), biological events that include morphogenesis, maintenance which is activated by starvation conditions associated with of tissue homeostasis, and elimination of harmful cells. deficiency of nutrients such as amino acids. Autophagy is Dysfunction of PCD leads to various diseases in humans, also known to be activated by hypoxic conditions and high including cancer and several degenerative diseases. Apop- temperatures. Autophagy is a process by which cells undergo tosis is not the only form of PCD. Recent studies have partial autodigestion (the term is derived from ancient Greek provided evidence that there is another mechanism of PCD, meaning to ‘eat oneself’) that prolongs survival for a short which is associated with the appearance of autophagosomes time under starvation conditions. It provides nutrients that are and depends on autophagy proteins. This form of cell death necessary to maintain cell viability. It has more recently been most likely corresponds to a process that has been shown that autophagy is also involved in the killing of bacteria that are ingested by cells.5,6 morphologically defined as autophagic PCD. The present The molecular basis of autophagy has been extensively review summarizes recent experimental evidence about studied, mainly in yeasts, by investigation of autophagy- autophagic PCD and discusses some aspects of this form defective mutants to identify the responsible genes (desig- of cell death, including the mechanisms that may distinguish nated as atg). It is currently known that the basic mechanism autophagic death from the process of autophagy involved in of autophagy has been well conserved during evolution from cell survival. the fact that diverse organisms, including yeasts, flies, and Cell Death and Differentiation (2005) 12, 1528–1534. mammals, all carry a similar set of atg genes, although there doi:10.1038/sj.cdd.4401777 are some significant differences between yeasts and higher eukaryotes. Autophagy is regulated by PI3 kinase type I and Keywords: cell death; autophagy; apoptosis; Bcl-2; Bax III. PI3 kinase type I is activated by growth factors like insulin and inhibits autophagy through PDK1 and AKT, which Abbreviations: PCD, programmed cell death; MEFs, mouse regulates mammalian target of rapamycin (mTOR). It is still embryonic fibroblasts; 3-MA, 3-methyladenine; WT, wild-type; unclear how activation of mTOR inhibits autophagy, but the Glud2, glutamate receptor d2 mechanism may involve phosphorylation of Atg13, which is part of a protein complex with Atg1, a serine/threonine kinase. Since mTOR is regulated by many other proteins, regulation of the process of autophagy is likely to be very complex. PI3 A Constantly Raised Concern for kinase type III, which includes Atg6 in its complex, promotes the nucleation of autophagic vesicles (Figure 1). Expansion Autophagic Death of autophagic vesicles is mediated by two ubiquitin-like Apoptosis, a form of programmed cell death (PCD), has conjugation systems: (1) the Atg12 pathway (involving attracted considerable attention over the last 15 years and Atg12 (ubiquitin-like), Atg7 (E1-like), Atg10 (E2-like), and a significant part of the molecular mechanisms involved Atg5) and (2) the Atg8 pathway (involving Atg8 (ubiquitin-like), has already been unveiled. However, there is considerable Atg7 (E1-like), Atg3 (E2-like), and Atg4) (Figure 1). In the evidence to suggest that PCD is not confined to apoptosis Atg12 pathway, Atg12 is conjugated to Atg5, while Atg8 and that other mechanisms may also operate. One of these is conjugated to phosphatidylethanolamine in the Atg8 mechanisms is the so-called ‘autophagic PCD’,1 which is a pathway. Another way to die: autophagic programmed cell death Y Tsujimoto and S Shimizu 1529 Figure 1 Diagram of the autophagic process. PI3 kinase type III and two ubiquitin-like conjugation systems are involved in the formation of autophagosomes. PE: phosphatidylethanolamine; ub: ubiquitin Autophagic death Autophagic cell death is mainly a morphologic definition (i.e. cell death associated with autophagosomes/autolysosomes), and there is still no conclusive evidence that a specific mechanism of autophagic death actually exists. However, it is quite conceivable that constitutive autophagy could eventually destroy a cell. This hypothesis as well as previous reports that cells with autophagic features often exist in regions where PCD is occurring seem to support the existence of autophagic cell death.7 One question that constantly arises, however, is whether autophagic activity in dying cells is the cause of death or is actually an attempt to prevent it. Morphological and histochemical studies cannot prove a causative relationship Figure 2 Electron micrograph of Bax/Bak-deficient MEFs with and without between the autophagic process and cell death. In fact, there exposure to etoposide. (a) Control cell and (b) etoposide (20 mM)-treated cell. have recently been strong arguments that autophagic activity The etoposide-treated cell contains many autophagosomes (arrows) in dying cells might actually be a survival mechanism. One reason why this issue has not been resolved is a lack propidium iodide (a marker of plasma membrane disruption), of a suitable experimental system to investigate autophagic findings which are compelling evidence of cell death when death. We recently found that cytotoxic stimuli activate taken together.8 Electron microscopy has revealed that drug- autophagic death in cells that are protected against apoptosis, treated Bax/Bak-deficient cells contain numerous double- such as those expressing antiapoptotic Bcl-2 or Bcl-x ,or L membrane vesicles8 (also see Figure 2), which have been those lacking both Bax and Bak (multidomain proapoptotic confirmed to be autophagosomes by the punctate distribution members of the Bcl-2 family that function as a gateway for a of GFP-LC3 (GFP-Atg8: a portion specifically concentrated variety of apoptotic signals).8 Lenardo’s group has also found on autophagosomes that is normally spread throughout the that cell lines such as L929 undergo autophagic death in the cytoplasm)8 (also see Figure 3). This nonapoptotic form of cell presence of z-VAD-fmk, a pancaspase inhibitor.9 death can be inhibited by suppressing autophagosome formation with autophagy inhibitors, such as 3-methyladenine Autophagic Programmed Death is an (3-MA) and wortmannin, or by silencing Atg5 and Atg6, as assessed by several different methods.8 Inhibition of cell Alternative to Apoptosis death has been convincingly demonstrated by detection of Bax/Bak-deficient mouse embryonic fibroblasts (MEFs) do improved clonogenicity8 (also see Figure 4). Thus, these not undergo apoptosis after exposure to a variety of apoptotic results indicate that autophagosome formation is required stimuli.10,11 Instead, we have found that these cells die in for cells to die after exposure to cytotoxic drugs, proving the a nonapoptotic manner when exposed to various cytotoxic existence of an alternative death mechanism to apoptosis that agents, such as etoposide, staurosporine, and thapsigargin. could be termed autophagic cell death. Independently, MEFs exposed to these agents show (1) loss of clonogenicity Lenardo’s group has also shown by studies on several cell (the ability to form colonies) and (2) positive staining with lines, including mouse L929 cells and human U937 cells, that Cell Death and Differentiation Another way to die: autophagic programmed cell death Y Tsujimoto and S Shimizu 1530 Figure 3 GFP-LC3 fluorescence in Bax/Bak-deficient MEFs. Bax/Bak-deficient MEFs were transfected with GFP-LC3 DNA and then cultured (a) without etoposide, (b) with etoposide (20 mM), and (c) in the absence of amino acids. Whereas untreated healthy cells show diffuse distribution of GFP-LC3, Bax/Bak- deficient MEFs exposed to etoposide or amino-acid depletion show a punctate distribution of GFP-LC3, indicating the formation of autophagosomes. LC3 is known to be concentrated
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