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Showing papers by "Guido Kroemer published in 2009"


Journal ArticleDOI
Lorenzo Galluzzi1, Lorenzo Galluzzi2, Lorenzo Galluzzi3, Stuart A. Aaronson4, John M. Abrams5, Emad S. Alnemri6, David W. Andrews7, Eric H. Baehrecke8, Nicolas G. Bazan9, Mikhail V. Blagosklonny10, Klas Blomgren11, Klas Blomgren12, Christoph Borner13, Dale E. Bredesen14, Dale E. Bredesen15, Catherine Brenner16, Maria Castedo2, Maria Castedo1, Maria Castedo3, John A. Cidlowski17, Aaron Ciechanover18, Gerald M. Cohen19, V De Laurenzi20, R De Maria21, Mohanish Deshmukh22, Brian David Dynlacht23, Wafik S. El-Deiry24, Richard A. Flavell25, Richard A. Flavell26, Simone Fulda27, Carmen Garrido2, Carmen Garrido28, Pierre Golstein2, Pierre Golstein16, Pierre Golstein29, Marie-Lise Gougeon30, Douglas R. Green, Hinrich Gronemeyer16, Hinrich Gronemeyer2, Hinrich Gronemeyer31, György Hajnóczky6, J. M. Hardwick32, Michael O. Hengartner33, Hidenori Ichijo34, Marja Jäättelä, Oliver Kepp2, Oliver Kepp1, Oliver Kepp3, Adi Kimchi35, Daniel J. Klionsky36, Richard A. Knight37, Sally Kornbluth38, Sharad Kumar, Beth Levine25, Beth Levine5, Stuart A. Lipton, Enrico Lugli17, Frank Madeo39, Walter Malorni21, Jean-Christophe Marine40, Seamus J. Martin41, Jan Paul Medema42, Patrick Mehlen16, Patrick Mehlen43, Gerry Melino19, Gerry Melino44, Ute M. Moll45, Ute M. Moll46, Eugenia Morselli3, Eugenia Morselli2, Eugenia Morselli1, Shigekazu Nagata47, Donald W. Nicholson48, Pierluigi Nicotera19, Gabriel Núñez36, Moshe Oren35, Josef M. Penninger49, Shazib Pervaiz50, Marcus E. Peter51, Mauro Piacentini44, Jochen H. M. Prehn52, Hamsa Puthalakath53, Gabriel A. Rabinovich54, Rosario Rizzuto55, Cecília M. P. Rodrigues56, David C. Rubinsztein57, Thomas Rudel58, Luca Scorrano59, Hans-Uwe Simon60, Hermann Steller61, Hermann Steller25, J. Tschopp62, Yoshihide Tsujimoto63, Peter Vandenabeele64, Ilio Vitale3, Ilio Vitale2, Ilio Vitale1, Karen H. Vousden65, Richard J. Youle17, Junying Yuan66, Boris Zhivotovsky67, Guido Kroemer3, Guido Kroemer2, Guido Kroemer1 
Institut Gustave Roussy1, French Institute of Health and Medical Research2, University of Paris-Sud3, Icahn School of Medicine at Mount Sinai4, University of Texas Southwestern Medical Center5, Thomas Jefferson University6, McMaster University7, University of Massachusetts Medical School8, LSU Health Sciences Center New Orleans9, Roswell Park Cancer Institute10, University of Gothenburg11, Boston Children's Hospital12, University of Freiburg13, Buck Institute for Research on Aging14, University of California, San Francisco15, Centre national de la recherche scientifique16, National Institutes of Health17, Technion – Israel Institute of Technology18, University of Leicester19, University of Chieti-Pescara20, Istituto Superiore di Sanità21, University of North Carolina at Chapel Hill22, New York University23, University of Pennsylvania24, Howard Hughes Medical Institute25, Yale University26, University of Ulm27, University of Burgundy28, Aix-Marseille University29, Pasteur Institute30, University of Strasbourg31, Johns Hopkins University32, University of Zurich33, University of Tokyo34, Weizmann Institute of Science35, University of Michigan36, University College London37, Duke University38, University of Graz39, Ghent University40, Trinity College, Dublin41, University of Amsterdam42, University of Lyon43, University of Rome Tor Vergata44, Stony Brook University45, University of Göttingen46, Kyoto University47, Merck & Co.48, Austrian Academy of Sciences49, National University of Singapore50, University of Chicago51, Royal College of Surgeons in Ireland52, La Trobe University53, University of Buenos Aires54, University of Padua55, University of Lisbon56, University of Cambridge57, University of Würzburg58, University of Geneva59, University of Bern60, Rockefeller University61, University of Lausanne62, Osaka University63, University of California, San Diego64, University of Glasgow65, Harvard University66, Karolinska Institutet67
TL;DR: A nonexhaustive comparison of methods to detect cell death with apoptotic or nonapoptotic morphologies, their advantages and pitfalls is provided and the importance of performing multiple, methodologically unrelated assays to quantify dying and dead cells is emphasized.
Abstract: Cell death is essential for a plethora of physiological processes, and its deregulation characterizes numerous human diseases Thus, the in-depth investigation of cell death and its mechanisms constitutes a formidable challenge for fundamental and applied biomedical research, and has tremendous implications for the development of novel therapeutic strategies It is, therefore, of utmost importance to standardize the experimental procedures that identify dying and dead cells in cell cultures and/or in tissues, from model organisms and/or humans, in healthy and/or pathological scenarios Thus far, dozens of methods have been proposed to quantify cell death-related parameters However, no guidelines exist regarding their use and interpretation, and nobody has thoroughly annotated the experimental settings for which each of these techniques is most appropriate Here, we provide a nonexhaustive comparison of methods to detect cell death with apoptotic or nonapoptotic morphologies, their advantages and pitfalls These guidelines are intended for investigators who study cell death, as well as for reviewers who need to constructively critique scientific reports that deal with cellular demise Given the difficulties in determining the exact number of cells that have passed the point-of-no-return of the signaling cascades leading to cell death, we emphasize the importance of performing multiple, methodologically unrelated assays to quantify dying and dead cells

2,218 citations


Journal ArticleDOI
TL;DR: It is shown that dying tumor cells release ATP, which then acts on P2X7 purinergic receptors from DCs and triggers the NOD-like receptor family, pyrin domain containing-3 protein (NLRP3)-dependent caspase-1 activation complex ('inflammasome'), allowing for the secretion of interleukin-1 β (IL-1β).
Abstract: The therapeutic efficacy of anticancer chemotherapies may depend on dendritic cells (DCs), which present antigens from dying cancer cells to prime tumor-specific interferon-gamma (IFN-gamma)-producing T lymphocytes. Here we show that dying tumor cells release ATP, which then acts on P2X(7) purinergic receptors from DCs and triggers the NOD-like receptor family, pyrin domain containing-3 protein (NLRP3)-dependent caspase-1 activation complex ('inflammasome'), allowing for the secretion of interleukin-1beta (IL-1beta). The priming of IFN-gamma-producing CD8+ T cells by dying tumor cells fails in the absence of a functional IL-1 receptor 1 and in Nlpr3-deficient (Nlrp3(-/-)) or caspase-1-deficient (Casp-1(-/-)) mice unless exogenous IL-1beta is provided. Accordingly, anticancer chemotherapy turned out to be inefficient against tumors established in purinergic receptor P2rx7(-/-) or Nlrp3(-/-) or Casp1(-/-) hosts. Anthracycline-treated individuals with breast cancer carrying a loss-of-function allele of P2RX7 developed metastatic disease more rapidly than individuals bearing the normal allele. These results indicate that the NLRP3 inflammasome links the innate and adaptive immune responses against dying tumor cells.

1,628 citations


Journal ArticleDOI
TL;DR: This article showed that spermidine, a natural polyamine whose intracellular concentration declines during human ageing, markedly extended the lifespan of yeast, flies and worms, and human immune cells.
Abstract: Ageing results from complex genetically and epigenetically programmed processes that are elicited in part by noxious or stressful events that cause programmed cell death. Here, we report that administration of spermidine, a natural polyamine whose intracellular concentration declines during human ageing, markedly extended the lifespan of yeast, flies and worms, and human immune cells. In addition, spermidine administration potently inhibited oxidative stress in ageing mice. In ageing yeast, spermidine treatment triggered epigenetic deacetylation of histone H3 through inhibition of histone acetyltransferases (HAT), suppressing oxidative stress and necrosis. Conversely, depletion of endogenous polyamines led to hyperacetylation, generation of reactive oxygen species, early necrotic death and decreased lifespan. The altered acetylation status of the chromatin led to significant upregulation of various autophagy-related transcripts, triggering autophagy in yeast, flies, worms and human cells. Finally, we found that enhanced autophagy is crucial for polyamine-induced suppression of necrosis and enhanced longevity.

1,230 citations


Journal ArticleDOI
30 Apr 2009-Nature
TL;DR: An emerging area of research unravels additional activities of p53 in the cytoplasm, where it triggers apoptosis and inhibits autophagy, which contribute to the mission of p 53 as a tumour suppressor.
Abstract: The principal tumour-suppressor protein, p53, accumulates in cells in response to DNA damage, oncogene activation and other stresses. It acts as a nuclear transcription factor that transactivates genes involved in apoptosis, cell cycle regulation and numerous other processes. An emerging area of research unravels additional activities of p53 in the cytoplasm, where it triggers apoptosis and inhibits autophagy. These previously unknown functions contribute to the mission of p53 as a tumour suppressor.

1,020 citations


Journal ArticleDOI
TL;DR: A central problem in immunology is to understand how the immune system determines whether cell death is immunogenic, tolerogenic or 'silent', which can result in autoimmunity.
Abstract: The immune system is routinely exposed to dead cells during normal cell turnover, injury and infection. Mechanisms must exist to discriminate between different forms of cell death in order to correctly eliminate pathogens and promote healing while avoiding responses to self, which can result in autoimmunity. However, an effective response against host tissue is also often needed to eliminate tumors following treatment with chemotherapeutic agents that trigger tumor cell death. Consequently, a central problem in immunology is to understand how the immune system determines whether cell death is immunogenic, tolerogenic or 'silent'.

1,009 citations


Journal ArticleDOI
TL;DR: Depletion of PERK, caspase‐8 or SNAREs had no effect on cell death induced by anthracyclines, yet abolished the immunogenicity of cell death, which could be restored by absorbing recombinant CRT to the cell surface.
Abstract: Dying tumour cells can elicit a potent anticancer immune response by exposing the calreticulin (CRT)/ERp57 complex on the cell surface before the cells manifest any signs of apoptosis. Here, we enumerate elements of the pathway that mediates pre-apoptotic CRT/ERp57 exposure in response to several immunogenic anticancer agents. Early activation of the endoplasmic reticulum (ER)-sessile kinase PERK leads to phosphorylation of the translation initiation factor eIF2α, followed by partial activation of caspase-8 (but not caspase-3), caspase-8-mediated cleavage of the ER protein BAP31 and conformational activation of Bax and Bak. Finally, a pool of CRT that has transited the Golgi apparatus is secreted by SNARE-dependent exocytosis. Knock-in mutation of eIF2α (to make it non-phosphorylatable) or BAP31 (to render it uncleavable), depletion of PERK, caspase-8, BAP31, Bax, Bak or SNAREs abolished CRT/ERp57 exposure induced by anthracyclines, oxaliplatin and ultraviolet C light. Depletion of PERK, caspase-8 or SNAREs had no effect on cell death induced by anthracyclines, yet abolished the immunogenicity of cell death, which could be restored by absorbing recombinant CRT to the cell surface.

682 citations


Journal ArticleDOI
TL;DR: The current state-of-the art suggests a complex relationship between cancer and deregulated autophagy that must be disentangled by further in-depth investigation.
Abstract: Multiple oncogenes (in particular phosphatidylinositol 3-kinase, PI3K; activated Akt1; antiapoptotic proteins from the Bcl-2 family) inhibit autophagy. Similarly, several tumor suppressor proteins (such as BH3-only proteins; death-associated protein kinase-1, DAPK1; the phosphatase that antagonizes PI3K, PTEN; tuberous sclerosic complex 1 and 2, TSC1 and TSC2; as well as LKB1/STK11) induce autophagy, meaning that their loss reduces autophagy. Beclin-1, which is required for autophagy induction acts as a haploinsufficient tumor suppressor protein, and other essential autophagy mediators (such as Atg4c, UVRAG and Bif-1) are bona fide oncosuppressors. One of the central tumor suppressor proteins, p53 exerts an ambiguous function in the regulation of autophagy. Within the nucleus, p53 can act as an autophagy-inducing transcription factor. Within the cytoplasm, p53 exerts a tonic autophagy-inhibitory function, and its degradation is actually required for the induction of autophagy. The role of autophagy in oncogenesis and anticancer therapy is contradictory. Chronic suppression of autophagy may stimulate oncogenesis. However, once a tumor is formed, autophagy inhibition may be a therapeutic goal for radiosensitization and chemosensitization. Altogether, the current state-of-the art suggests a complex relationship between cancer and deregulated autophagy that must be disentangled by further in-depth investigation.

410 citations


Journal ArticleDOI
TL;DR: The permeabilization of mitochondrial membranes determines whether cells will succumb to or survive the injury, and represents a 'point of no return' in mitochondrial cell death, and is therefore an attractive target for the development of new neuroprotective interventions.
Abstract: Acute neurological conditions such as cerebrovascular diseases and trauma are associated with irreversible loss of neurons and glial cells. Severe or prolonged injury results in uncontrollable cell death within the core of lesions. Conversely, cells that are less severely damaged succumb in a relatively slow fashion, frequently via the intrinsic pathway of cell death, through the deterioration of mitochondrial functions. The permeabilization of mitochondrial membranes determines whether cells will succumb to or survive the injury, and represents a 'point of no return' in mitochondrial cell death. It is therefore an attractive target for the development of new neuroprotective interventions.

376 citations


Journal ArticleDOI
TL;DR: Current knowledge is reviewed on the dual role of autophagy as an anti- and pro-tumor mechanism, which would represent a major therapeutic target for chemosensitization.

354 citations


Journal ArticleDOI
TL;DR: IP3R is identified as a new regulator of the Beclin 1 complex that may bridge signals converging on the ER and initial phagophore formation.
Abstract: The inositol 1,4,5-trisphosphate receptor (IP(3)R) is a major regulator of apoptotic signaling. Through interactions with members of the Bcl-2 family of proteins, it drives calcium (Ca(2+)) transients from the endoplasmic reticulum (ER) to mitochondria, thereby establishing a functional and physical link between these organelles. Importantly, the IP(3)R also regulates autophagy, and in particular, its inhibition/depletion strongly induces macroautophagy. Here, we show that the IP(3)R antagonist xestospongin B induces autophagy by disrupting a molecular complex formed by the IP(3)R and Beclin 1, an interaction that is increased or inhibited by overexpression or knockdown of Bcl-2, respectively. An effect of Beclin 1 on Ca(2+) homeostasis was discarded as siRNA-mediated knockdown of Beclin 1 did not affect cytosolic or luminal ER Ca(2+) levels. Xestospongin B- or starvation-induced autophagy was inhibited by overexpression of the IP(3)R ligand-binding domain, which coimmunoprecipitated with Beclin 1. These results identify IP(3)R as a new regulator of the Beclin 1 complex that may bridge signals converging on the ER and initial phagophore formation.

282 citations


Journal ArticleDOI
TL;DR: It is reported that Sestrin2, a novel p53 target gene, is involved in the induction of autophagy and acts as a positive regulator of Autophagy in p53-proficient cells.
Abstract: The oncosuppressor protein p53 regulates autophagy in a dual fashion. The pool of cytoplasmic p53 protein represses autophagy in a transcription-independent fashion, while the pool of nuclear p53 stimulates autophagy through the transactivation of specific genes. Here we report the discovery that Sestrin2, a novel p53 target gene, is involved in the induction of autophagy. Depletion of Sestrin2 by RNA interference reduced the level of autophagy in a panel of p53-sufficient human cancer cell lines responding to distinct autophagy inducers. In quantitative terms, Sestrin2 depletion was as efficient in preventing autophagy induction as was the depletion of Dram, another p53 target gene. Knockout of either Sestrin2 or Dram reduced autophagy elicited by nutrient depletion, rapamycin, lithium or thapsigargin. Moreover, autophagy induction by nutrient depletion or pharmacological stimuli led to an increase in Sestrin2 expression levels in p53-proficient cells. In strict contrast, the depletion of Sestrin2 or Dram failed to affect autophagy in p53-deficient cells and did not modulate the inhibition of baseline autophagy by a cytoplasmic p53 mutant that was reintroduced into p53-deficient cells. We conclude that Sestrin2 acts as a positive regulator of autophagy in p53-proficient cells.

Journal ArticleDOI
TL;DR: It is described that multiple distinct anticancer drugs reduce the intracellular concentration of ATP before and during the manifestation of apoptotic characteristics such as the dissipation of the mitochondrial transmembrane potential and the exposure of phosphatidylserine residues on the plasma membrane.
Abstract: Chemotherapy can induce anticancer immune responses. In contrast to a widely extended prejudice, apoptotic cell death is often more efficient in eliciting a protective anticancer immune response than necrotic cell death. Recently, we have found that purinergic receptors of the P2X7 type are required for the anticancer immune response induced by chemotherapy. ATP is the endogenous ligand that has the highest affinity for P2X7. Therefore, we investigated the capacity of a panel of chemotherapeutic agents to induce ATP release from cancer cells. Here, we describe that multiple distinct anticancer drugs reduce the intracellular concentration of ATP before and during the manifestation of apoptotic characteristics such as the dissipation of the mitochondrial transmembrane potential and the exposure of phosphatidylserine residues on the plasma membrane. Indeed, as apoptosis progresses, intracellular ATP concentrations decrease, although even advanced-stage apoptotic cells still contain sizeable ATP levels. Only when cells enter secondary necrosis, the ATP concentration falls to undetectable levels. Concomitantly, a wide range of chemotherapeutic agents causes the release of ATP into the extracellular space as they induce tumor cell death. Hence, ATP release is a general correlate of apoptotic cell death induced by conventional anticancer therapies.

Journal ArticleDOI
TL;DR: The data suggest that acinar cell vacuolization in pancreatitis is mediated by an endotoxemia-induced inhibition of the late stage of autophagy as well as human patients with alcoholic pancreatitis, which points to a crucial role for Lamp-2 and Autophagy in pancreatic acinar Cell death.

Journal ArticleDOI
23 Dec 2009
TL;DR: Results point to an essential role of protein hypoacetylation in autophagy control and in the regulation of longevity.
Abstract: Although autophagy has widely been conceived as a self-destructive mechanism that causes cell death, accumulating evidence suggests that autophagy usually mediates cytoprotection, thereby avoiding the apoptotic or necrotic demise of stressed cells. Recent evidence produced by our groups demonstrates that autophagy is also involved in pharmacological manipulations that increase longevity. Exogenous supply of the polyamine spermidine can prolong the lifespan of (while inducing autophagy in) yeast, nematodes and flies. Similarly, resveratrol can trigger autophagy in cells from different organisms, extend lifespan in nematodes, and ameliorate the fitness of human cells undergoing metabolic stress. These beneficial effects are lost when essential autophagy modulators are genetically or pharmacologically inactivated, indicating that autophagy is required for the cytoprotective and/or anti-aging effects of spermidine and resveratrol. Genetic and functional studies indicate that spermidine inhibits histone acetylases, while resveratrol activates the histone deacetylase Sirtuin 1 to confer cytoprotection/longevity. Although it remains elusive whether the same histones (or perhaps other nuclear or cytoplasmic proteins) act as the downstream targets of spermidine and resveratrol, these results point to an essential role of protein hypoacetylation in autophagy control and in the regulation of longevity.

Journal ArticleDOI
TL;DR: It is surmised that the response to cellular stress like chemotherapy or ionizing irradiation, dictates the immunological response to dying cells and that this immune response in turn determines the clinical outcome of anticancer therapies.
Abstract: It is still enigmatic under which circumstances cellular demise induces an immune response or rather remains immunologically silent. Moreover, the question remains open under which circumstances apoptotic, autophagic or necrotic cells are immunogenic or tolerogenic. Although apoptosis appears to be morphologically homogenous, recent evidence suggests that the pre-apoptotic surface-exposure of calreticulin may dictate the immune response to tumor cells that succumb to anticancer treatments. Moreover, the release of high-mobility group box 1 (HMGB1) during late apoptosis and secondary necrosis contributes to efficient antigen presentation and cytotoxic T-cell activation because HMGB1 can bind to Toll like receptor 4 on dendritic cells, thereby stimulating optimal antigen processing. Cell death accompanied by autophagy also may facilitate cross priming events. Apoptosis, necrosis and autophagy are closely intertwined processes. Often, cells manifest autophagy before they undergo apoptosis or necrosis, and apoptosis is generally followed by secondary necrosis. Whereas apoptosis and necrosis irreversibly lead to cell death, autophagy can clear cells from stress factors and thus facilitate cellular survival. We surmise that the response to cellular stress like chemotherapy or ionizing irradiation, dictates the immunological response to dying cells and that this immune response in turn determines the clinical outcome of anticancer therapies. The purpose of this review is to summarize recent insights into the immunogenicity of dying tumor cells as a function of the cell death modality.

Journal ArticleDOI
TL;DR: It is predicted that targeting the autophagy cascade may provide a therapeutic strategy for achieving robust cross-priming of viral and tumor-specific CD8+ T cells.
Abstract: Cross-presentation of cell-associated antigen is important in the priming of CD8(+) T-cell responses to proteins that are not expressed by antigen-presenting cells (APCs). In vivo, dendritic cells are the main cross-presenting APC, and much is known regarding their ability to capture and process cell-associated antigen. In contrast, little is known about the way death effector pathways influence the efficiency of cross-priming. Here, we compared two important mechanisms of programmed cell death: classical apoptosis, as it occurs in wild-type (WT) fibroblasts, and caspase-independent cell death, which occurs with increased features of autophagy in Bax/Bak(-/-) fibroblasts. We assessed virally infected WT and Bax/Bak(-/-) fibroblasts as a source of cell-associated antigen. We found that immunization with cells undergoing autophagy before cell death was superior in facilitating the cross-priming of antigen-specific CD8(+) T cells. Strikingly, silencing of Atg5 expression inhibited priming. We interpret this to be a novel form of 'immunogenic death' with the enhanced priming efficiency being a result of persistent MHC I cross-presentation and the induction of type I interferons. These results offer the first molecular evidence that catabolic pathways, including autophagy, influence the efficiency of cross-priming. We predict that targeting the autophagy cascade may provide a therapeutic strategy for achieving robust cross-priming of viral and tumor-specific CD8(+) T cells.

Journal ArticleDOI
TL;DR: The manifold nature of AIF in cell life and death is discussed, with particular emphasis of its roles in vivo.
Abstract: Since its discovery nearly a decade ago, apoptosis-inducing factor (AIF) has had anything but a staid and uneventful existence. AIF was originally described as a mitochondrial intermembrane protein that, after apoptosis induction, can translocate to the nucleus and trigger chromatin condensation and DNA fragmentation. Over the years, an AIF-mediated caspase-independent cell death pathway has been defined. Rather than functioning as a general component of the cell death machinery, AIF is required for specific cell death pathways, including lethal responses to excitotoxins such as N-methyl-d-aspartate and glutamate, the DNA-alkylating agent N-methyl-N'-nitro-N-nitroso-guanidine, hypoxia–ischemia, or growth factor deprivation. Also, important roles of AIF in mitochondrial metabolism and redox control, and more recently in obesity and diabetes, have been discovered. Much of our knowledge has come from studies of AIF orthologs in model organisms, Saccharomyces cerevisiae, Caenorhabditis elegans, Drosophila melanogaster, and mice, which have also highlighted the importance of AIF in animal physiology and human pathology. Here, we discuss the manifold nature of AIF in cell life and death, with particular emphasis of its roles in vivo.

Journal ArticleDOI
TL;DR: A consensus is emerging that autophagy is largely a cell death impostor which, in reality, functions primarily to promote cellular and organismal health.
Abstract: Although strictly speaking, the term autophagy merely means ‘self-eating’, many presume that this cellular self-eating is inevitably a form of cellular self-destruction. Indeed, within the cell death research field, autophagy has also long been defined as a form of non-apoptotic, or type II, programmed cell death. However, as revealed in this issue of Cell Death and Differentiation, which contains nine review papers on the topic of Autophagy in Aging, Disease and Death1–9 and one article outlining the recommendations of the Nomenclature Committee on Cell Death 2009,10 a consensus is emerging that autophagy is largely a cell death impostor which, in reality, functions primarily to promote cellular and organismal health. Five of the papers in this series describe unequivocal beneficial functions of autophagy in the life of a cell or eukaryotic organism. Sarkar et al.1 discuss the beneficial effects of mTOR-dependent and mTOR-independent induction of autophagy in enhanced neuronal clearance and reduced neurotoxicity of mutant huntingtin fragment and other polyglutamine expansion proteins in cultured cells and animal models. Perlmutter2 discusses the role of autophagy in the disposal of mutant α-1-antitrypsin, a toxic aggregate-prone protein that accumulates in the endoplasmic reticulum of hepatocytes and causes liver inflammation and carcinogenesis. Orvedahl and Levine3 discuss the immune signaling mechanisms that activate autophagy, the different effector mechanisms of autophagy in immunity, and the potential for exploiting the autophagy pathway in the treatment of infectious diseases. Lunemann and Munz4 provide a more focused review on one important aspect of autophagy in immunity, namely, its role in delivering cytoplasmic material to MHC Class II antigen-loading compartments for regulation of adaptive immune responses. Finally, Vellai5 discusses the compelling genetic evidence in Caenorhabditis elegans and Drosophila models that autophagy functions as an antiaging mechanism, presumably by degrading aberrant cytosolic macromolecules and organelles. Thus, the delivery function of autophagy – either to the lysosome for degradation or to other cellular compartments for immune activation – is important in protection against aging, neurodegenerative diseases, α-1-antitrypsin deficiency, and infectious diseases and indeed, clinical trials with autophagy-inducing agents are now being planned for the prevention of aging, and treatment of certain neurodegenerative and infectious diseases. In the case of lysosomal delivery, ‘self-eating’ (as well as xenophagy, the digestion of microbes) certainly does occur. However, it is not part of a program of cellular self-destruction that leads to cell death. Rather, it is a mechanism by which the cell rids itself of potentially harmful constituents, and thereby helps to maintain its normal functioning. Thus, after years of being (mis)interpreted as a cell death process, the study summarized in the review papers in this issue shed important light on the true identity of autophagy – which is, in part, an adaptive cellular housekeeping mechanism. Two other papers in this review series describe a more complex interplay between autophagy and disease, in particular, cancer and heart disease, where autophagy may have context-dependent beneficial or detrimental roles.6,7 Maiuri et al.6 review the emerging paradigm that oncogenes inhibit autophagy, whereas tumor-suppressor genes induce autophagy, as well as a notable exception to this paradigm, which is the inhibition of autophagy by the cytoplasmic form of the tumor-suppressor protein, p53. The authors propose that chronic suppression of autophagy promotes oncogenesis, perhaps through genomic instability, defective cell growth regulation, and/or defective regulation of endogenous genotoxic stress. However, they also note that enhanced autophagy may constitute a mechanism utilized by tumor cells to survive hypoxic, metabolic, detachment-induced, or chemotherapeutic stress. Thus, ironically, the malevolent function of autophagy in cancer, if it has one, is not a role in cell death, but rather, a role in tumor cell survival. Given the duality of autophagy’s function in tumor suppression and tumor cell survival, as the authors’ state, the ‘relationship between cancer and autophagy cannot be reduced to a simple formulation’ and further studies are needed to determine if, when, and how clinical oncologists should turn autophagy on or off. In the heart, it is still unclear whether autophagy is a protective or detrimental response in responses to stresses such as ischemia/reperfusion and in cardiovascular diseases such as cardiac hypertrophy and heart failure. Nishida et al.7 provide a comprehensive review of this controversy, high-lighting the evidence from cardiac-specific atg5-deficient mice that autophagy protects cardiomyocytes from pressure over-laod or from isoproterenol stimulation (which contrasts with evidence from beclin 1-deficient mice) and the conflicting evidence that autophagy may mediate either cell survival or cell death during ischemia/reperfusion. Future studies in mouse models with cardiomyocyte-deficient autophagy may be useful in delineating the functions of autophagy in heart disease. However, given the limitations of mouse models of cardiac disease, a greater challenge will be to figure out if, when, and how cardiologists should regulate autophagy in patients with heart disease. With the exception of the mention of a possible role of excessive autophagy in the death of cardiomyocytes during ischemia/reperfusion injury, the papers in this issue that deal with autophagy in aging or disease underscore an identity of autophagy that is quite distinct from a cell death execution pathway. The picture that emerges is that the ‘core identity’ of autophagy is one of a cellular pathway that is cytoprotective. The pathway protects cells against the accumulation of damaged organelles, protein aggregates, and microbes; protects cells against oncogenesis; protects cells against cancer therapies, protects cardiac cells against hemodynamic stress; and protects infected cells by activating immune defenses. Thus, the frequent presence of autophagy in dying cells may represent a failed attempt of cytoprotection, rather than a mechanistic contribution to cell death; hence, we propose that autophagy is largely a ‘cell death impostor.’ Yet, the controversy remains as to whether in some circumstances autophagy is not merely a cell death impostor, but a bona fide mechanism of cell death. The Nomenclature Committee on Cell Death 2009 defines ‘autophagic cell death’ as a set of morphological features that ‘define cell death occurring with autophagy,’ noting that this term ‘may misleadingly suggest a form of death occurring through autophagy, as this process often promotes cell survival.’10 However, two papers in this issue review several examples of cell death by (not just with) autophagy; Scarlatti et al.8 discuss the evidence in mammalian cells and Kourtis and Tavernakis discuss the evidence in model organisms.8,9 In cultured mammalian cells, cell death by canonical autophagy (defined as death that is reduced by genetic inactivation of autophagy genes including beclin 1) has been reported primarily (but not exclusively) in cells that are deficient in apoptosis, either by the virtue of bax/bak deletion or caspase inhibition. Autophagy has also been described to be genetically upstream of apoptosis in the setting of HIV envelope protein triggered T lymphocyte death. Further, some death-inducing stimuli, such as the Parkinson neurotoxin, 1-methyl-4-phenylpyridiunium, and resveratrol reportedly induce cell death by non-canonical autophagy, which is independent of beclin 1 (a gene involved in autophagosome initiation), but requires other autophagy genes involved in autophagosome expansion and completion. In vivo, there are two examples to date in model organisms where knockdown/knockout of autophagy genes retards cell death, in the involuting Drosophila melanogaster salivary gland and in nematodes with hyperactive ion channels that undergo necrotic neuronal cell death. Direct induction of autophagy by overexpression of the Atg1 kinase has also been shown to be sufficient to kill fat and salivary gland cells in Drosophila. It is not yet clear how to reconcile the few examples of ‘cell death by autophagy’ with the larger number of studies in which autophagy suppression by genetic knockout/knockdown of essential autophagy genes increases cell death (reviewed in Scarlatti et al.,8 Kourtis and Tavernakis9 and Maiuri et al.11), indicating a prosurvival function of autophagy. Further, as noted by Scarlatti et al.,8 the evidence for cell death by autophagy remains to be demonstrated in mammals; in fact, embryonic mice lacking autophagy genes, including ambra1, beclin 1, and atg5, have been shown to have increased, not decreased, numbers of apoptotic cells (reviewed in Cecconi and Levine12). Thus, although it is certainly possible that autophagy is not always a cell death impostor, the majority of studies discussed in this issue of Cell Death and Differentiation (and recently reviewed elsewhere) suggest that the primary identity of autophagy lies elsewhere, namely, in cytoprotection. It will be important to further unravel the mysteries of the complex interplay between autophagy and cell death, but arguably, it may be even more important to further unravel the relationships between autophagy, aging, disease, and cell survival. The review papers in this series provide an excellent point of departure for meeting both of these scientific challenges.

Journal ArticleDOI
TL;DR: Mitochondrion-targeted agents such as BA hold great promise as a novel approach to overcome certain forms of drug resistance in human cancers.

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TL;DR: Yeast constitutes an excellent model organism to delineate phylogenetically conserved pathways leading to apoptotic or necrotic cell death and can be used to identify pharmacological and genetic modulators of cell death pathways that are relevant for human disease.

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TL;DR: Two members of the receptor-interacting serine-threonine kinase (RIP) family, RIP1 and RIP3, have been demonstrated to control the switch between apoptotic and necrotic cell death.
Abstract: Some lethal stimuli can induce either apoptosis or necrosis, depending on the cell type and/or experimental setting. Until recently, the molecular bases of this phenomenon were largely unknown. Now, two members of the receptor-interacting serine-threonine kinase (RIP) family, RIP1 and RIP3, have been demonstrated to control the switch between apoptotic and necrotic cell death. Some mechanistic details, however, remain controversial.

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TL;DR: In animal models of acute neuronal injury, the inhibition of caspases, apoptosis-inducing factor (AIF) and other apoptotic effectors can confer significant neuroprotection and are proposed as novel strategies of inhibiting post-mitochondrial apoptosis in neurons.

Journal ArticleDOI
TL;DR: The release of high mobility group box 1 protein (HMGB1) during late apoptosis promotes antigen processing by dendritic cells and hence contributes to efficient antigen presentation and cytotoxic T-cell activation.
Abstract: Purpose of reviewIt is an ongoing conundrum under which circumstances cellular demise induces an immune response and whether apoptotic or necrotic cells are intrinsically immunogenic or tolerogenic. This review summarizes recent insights in the immunogenicity of dying tumor cells.Recent findingsAlth

Journal ArticleDOI
25 Feb 2009-PLOS ONE
TL;DR: The Warburg effect might directly contribute to the initiation of cancer formation - not only by enhanced glycolysis - but also via decreased respiration in the presence of oxygen, which suppresses apoptosis.
Abstract: Background Otto Warburg observed that cancer cells are often characterized by intense glycolysis in the presence of oxygen and a concomitant decrease in mitochondrial respiration. Research has mainly focused on a possible connection between increased glycolysis and tumor development whereas decreased respiration has largely been left unattended. Therefore, a causal relation between decreased respiration and tumorigenesis has not been demonstrated.

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TL;DR: Malorni et al. further corroborate this notion by showing that type 2 transglutaminase (TG2) is essential for the correct assembly/function of ANT1, and that, at least in some experimental settings, TG2 might be required to enable and/or stabilize the pro-apoptotic association of Bax with ANT 1.
Abstract: Lethal mitochondrial membrane permeabilization has been depicted as the result of two fundamentally distinct processes, namely primary mitochondrial outer membrane permeabilization (MOMP) versus permeability transition (PT) ignited at the level of the mitochondrial inner membrane. MOMP and PT have been connected to apoptosis and necrosis, respectively. Moreover, it has been thought that MOMP was mediated by pro-apoptotic multidomain proteins of the Bcl-2 family (Bax and Bak), which would operate near-to-independently from the permeability transition pore complex (PTPC) composed by voltage-dependent anion channel (VDAC), adenine nucleotide translocase (ANT) and cyclophilin D. A recent paper in Molecular and Cellular Biology now reveals the obligate contribution of one particular ANT isoform to the execution of developmental and homeostatic cell death in Caenorhabditis elegans. The physical and functional interaction between CED-9, the sole multidomain Bcl-2 protein of C. elegans, and ANT emphasizes the existence of an intricate, phylogenetically conserved crosstalk between Bcl-2 family proteins and constituents of the PTPC. In this issue of Cell Death and Differentiation, Malorni et al. further corroborate this notion by showing that type 2 transglutaminase (TG2) is essential for the correct assembly/function of ANT1, and that, at least in some experimental settings, TG2 might be required to enable and/or stabilize the pro-apoptotic association of Bax with ANT1.

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TL;DR: It is shown that inhibition of the UPR by knockout of XBP-1 causes a massive increase in autophagy, enhances clearance of superoxide dismutase 1 (SOD1) aggregates, and delays the development of amyotrophic lateral sclerosis.
Abstract: Cellular defense mechanisms, including the unfolded protein response (UPR) and autophagy, attempt to resolve toxic protein aggregates, which are common denominators of neurodegenerative diseases. In this issue of Genes & Development, Hetz and colleagues (pp. 2294-2306) surprisingly show that inhibition of the UPR by knockout of XBP-1 causes a massive increase in autophagy, enhances clearance of superoxide dismutase 1 (SOD1) aggregates, and delays the development of amyotrophic lateral sclerosis. These findings suggest the existence of a homeostatic-if not hormetic-balance between distinct cellular defense mechanisms.

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13 Jul 2009
TL;DR: In this paper, the authors present a new long-lived yeast deletion mutation,afo1 (for aging factor one), that confers a 60% increase in replicative lifespan.
Abstract: Yeast mother cell-specific aging constitutes a model of replicative aging as it occurs in stem cell populations of higher eukaryotes. Here, we present a new long-lived yeast deletion mutation,afo1 (for aging factor one), that confers a 60% increase in replicative lifespan. AFO1/MRPL25 codes for a protein that is contained in the large subunit of the mitochondrial ribosome. Double mutant experiments indicate that the longevity-increasing action of the afo1 mutation is independent of mitochondrial translation, yet involves the cytoplasmic Tor1p as well as the growth-controlling transcription factor Sfp1p. In their final cell cycle, the long-lived mutant cells do show the phenotypes of yeast apoptosis indicating that the longevity of the mutant is not caused by an inability to undergo programmed cell death. Furthermore, the afo1 mutation displays high resistance against oxidants. Despite the respiratory deficiency the mutant has paradoxical increase in growth rate compared to generic petite mutants. A comparison of the single and double mutant strains for afo1 and fob1 shows that the longevity phenotype of afo1 is independent of the formation of ERCs (ribosomal DNA minicircles). AFO1/MRPL25 function establishes a new connection between mitochondria, metabolism and aging.

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TL;DR: The authors show that ligation of viral RNA sensors, such as RIG-I or MDA-5, by viral RNA mimetics triggers mitochondrial apoptosis in human melanoma cells in an IFN-independent fashion, suggesting that tumor cell killing and immunostimulation may synergize for optimal anticancer immunochemotherapy.
Abstract: Conventional chemotherapeutics may induce immunogenic cancer cell death or stimulate immune effectors via so-called off-target effects. The study by Besch et al. in this issue of the JCI now demonstrates that agents designed to stimulate the innate immune system by activating intracellular pattern recognition receptors can kill cancer cells in a direct, cell-autonomous fashion (see the related article beginning on page 2399). The authors show that ligation of viral RNA sensors, such as RIG-I or MDA-5, by viral RNA mimetics triggers mitochondrial apoptosis in human melanoma cells in an IFN-independent fashion. The data suggest that tumor cell killing and immunostimulation may synergize for optimal anticancer immunochemotherapy.

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TL;DR: It is postulate that obligate intracellular pathogens have developed a variety of strategies to subvert CRT exposure, thereby avoiding immunogenic cell death.
Abstract: While physiological cell death is non-immunogenic, pathogen induced cell death can be immunogenic and hence stimulate an immune response against antigens that derive from dying cells and are presented by dendritic cells (DCs). The obligate immunogenic “eat-me” signal generated by dying cells consists in the exposure of calreticulin (CRT) at the cell surface. This particular “eat-me” signal, which facilitates engulfment by DCs, can only be found on cells that succumb to immunogenic apoptosis, while it is not present on cells dying in an immunologically silent fashion. CRT normally resides in the lumen of the endoplasmic reticulum (ER), yet can translocate to the plasma membrane surface through a complex pathway that involves elements of the ER stress response (e.g., the eIF2α-phosphorylating kinase PERK), the apoptotic machinery (e.g., caspase-8 and its substrate BAP31, Bax, Bak), the anterograde transport from the ER to the Golgi apparatus, and SNARE-dependent exocytosis. A large panoply of viruses encode...

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26 Feb 2009-Oncogene
TL;DR: Results support the contention that constitutively active ATM accounts for the activation of NF-κB in high-risk MDS and AML, and induced the induction of apoptosis.
Abstract: The anti-apoptotic transcription factor nuclear factor-kappaB (NF-kappaB) is constitutively activated in CD34(+) myeloblasts from high-risk myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) patients. Inhibition of NF-kappaB by suppressing the canonical NF-kappaB activation pathway, for instance by knockdown of the three subunits of the inhibitor of NF-kappaB (I kappaB) kinase (IKK) complex (IKK1, IKK2 and NEMO) triggers apoptosis in such cells. Here, we show that an MDS/AML model cell line exhibits a constitutive interaction, within the nucleus, of activated, S1981-phosphorylated ataxia telangiectasia mutated (ATM) with NEMO. Inhibition of ATM with two distinct pharmacological inhibitors suppressed the activating autophosphorylation of ATM, blocked the interaction of ATM and NEMO, delocalized NEMO as well as another putative NF-kappaB activator, PIDD, from the nucleus, abolished the activating phosphorylation of the catalytic proteins of the IKK complex (IKK1/2 on serines 176/180), enhanced the expression of I kappaB alpha and caused the relocalization of NF-kappaB from the nucleus to the cytoplasm, followed by apoptosis. Knockdown of ATM with small-interfering RNAs had a similar effect that could not be enhanced by knockdown of NEMO, PIDD and the p65 NF-kappaB subunit, suggesting that an ATM inhibition/depletion truly induced apoptosis through inhibition of the NF-kappaB system. Pharmacological inhibition of ATM also induced the nucleocytoplasmic relocalization of p65 in malignant myeloblasts purified from patients with high-risk MDS or AML, correlating with the induction of apoptosis. Altogether, these results support the contention that constitutively active ATM accounts for the activation of NF-kappaB in high-risk MDS and AML.