Special Issue "Autophagy"
Quicklinks
A special issue of Cells (ISSN 2073-4409).
Deadline for manuscript submissions: closed (30 April 2012)
Special Issue Editor
Guest Editor
Dr. Anne Hamacher-Brady
Lysosomal Systems Biology, German Cancer Research Center (DKFZ) and BioQuant, INF 267, 69120 Heidelberg, Germany
Website: http://bradylabs.bioquant.uni-heidelberg.de
E-Mail: a.hamacher@dkfz.de
Phone: +49 6221 5451322
Interests: autophagy; programmed cell death; apoptosis; lysosomes; cell biology; cancer research; cardiovascular disease
Special Issue Information
Dear Colleagues,
Since the description of its molecular machinery began in the late 1990s, our understanding of autophagy, the process of intracellular (self-)digestion via lysosomes, has made an exceptional progress. Today, autophagy is recognized as an integral component of cellular physiology and pathophysiology. Autophagy has evolved from being regarded as a mechanism for the degradation of random cellular components to a heterogeneous and highly regulated process, capable of specificity. Through the degradation of a large variety of substrates, including proteins, protein aggregates, organelles, and intracellular pathogens, autophagy influences virtually all vital cellular functions and signaling pathways. Consequently, autophagy is intimately connected with cellular homeostasis and development and progression of diseases such as cancer, neurodegeneration, infection, and autoimmune disorders.
This Special Issue offers an Open Access forum that aims at bringing together a collection of original research and review articles addressing the expanding field of autophagy. To that end we are welcoming contributions which may cover molecular machinery, substrate specificity, regulation of autophagy and its crosstalk with essential cell signaling programs, in the context of the cell’s homeostatic and stress signaling. We hope to provide a stimulating resource for the fascinating subject of autophagy.
Dr. Anne Hamacher-Brady
Guest Editor
Submission
Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. Papers will be published continuously (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.
Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are refereed through a peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed Open Access quarterly journal published by MDPI.
Please visit the Instructions for Authors page before submitting a manuscript. For the first couple of issues the Article Processing Charge (APC) will be waived for well-prepared manuscripts.
English correction and/or formatting fees of 250 CHF (Swiss Francs) will be charged in certain cases for those articles accepted for publication that require extensive additional formatting and/or English corrections.
Keywords
- autophagy
- autophagosomes
- lysosomes
- degradation
- ubiquitin
- p62
- mitophagy
- programmed cell death
- reactive oxygen species
- metabolism
Published Papers (20 papers)
|
Received: 10 May 2012; in revised form: 3 June 2012 / Accepted: 12 June 2012 / Published: 20 June 2012
Show/Hide Abstract
| Download PDF Full-text (590 KB) | Download XML Full-text
Abstract: Macroautophagy has important physiological roles and its cytoprotective or detrimental function is compromised in various diseases such as many cancers and metabolic diseases. However, the importance of autophagy for cell responses has also been demonstrated in many other physiological and pathological situations. In this review, we discuss some of the recently discovered mechanisms involved in specific and unspecific autophagy related to mitochondrial dysfunction and organelle degradation, lipid metabolism and lipophagy as well as recent findings and evidence that link autophagy to unconventional protein secretion.
|
|
Received: 16 May 2012; in revised form: 13 June 2012 / Accepted: 14 June 2012 / Published: 25 June 2012
Show/Hide Abstract
| Download PDF Full-text (709 KB) | Download XML Full-text
Abstract: Autophagy is an intracellular degradation pathway for long-lived proteins and organelles. This process is activated above basal levels upon cell intrinsic or environmental stress and dysregulation of autophagy has been linked to various human diseases, including those caused by viral infection. Many viruses have evolved strategies to directly interfere with autophagy, presumably to facilitate their replication or to escape immune detection. However, in some cases, modulation of autophagy appears to be a consequence of the virus disturbing the cell’s metabolic signaling networks. Here, we summarize recent advances in research at the interface of autophagy and viral infection, paying special attention to strategies that human tumor viruses have evolved.
|
|
Received: 23 May 2012; in revised form: 19 June 2012 / Accepted: 20 June 2012 / Published: 29 June 2012
Show/Hide Abstract
| Download PDF Full-text (93 KB) | Download XML Full-text
Abstract: Autophagy is a process of cellular self-degradation and is a major pathway for elimination of cytoplasmic material by the lysosomes. Autophagy is responsible for the degradation of damaged organelles and protein aggregates and therefore plays a significant role in cellular homeostasis. Despite the initial belief that autophagy is a nonselective bulk process, there is growing evidence during the last years that sequestration and degradation of cellular material by autophagy can be accomplished in a selective and specific manner. Given the role of autophagy and selective autophagy in several disease related processes such as tumorigenesis, neurodegeneration and infections, it is very important to dissect the molecular mechanisms of selective autophagy, in the context of the system and the organism. An excellent genetically tractable model organism to study autophagy is Drosophila, which appears to have a highly conserved autophagic machinery compared with mammals. However, the mechanisms of selective autophagy in Drosophila have been largely unexplored. The aim of this review is to summarize recent discoveries about the selectivity of autophagy in Drosophila.
|
|
Received: 9 May 2012; in revised form: 14 June 2012 / Accepted: 19 June 2012 / Published: 4 July 2012
Show/Hide Abstract
| Download PDF Full-text (235 KB) | Download XML Full-text
Abstract: The budding yeast Saccharomyces cerevisiae responds to nutritional stress through the regulated activities of signaling pathways mediating autophagy and other conserved cellular processes. Autophagy has been studied intensely in yeast, where over 30 autophagy-related genes have been identified with defined roles enabling the formation of autophagic vesicles and their subsequent trafficking to the central yeast vacuole. Much less, however, is known regarding the regulatory mechanisms through which autophagy is integrated with other yeast stress responses. Nitrogen limitation initiates autophagy and pseudohyphal growth in yeast, the latter being a fascinating stress response characterized by the formation of multicellular chains or filaments of elongated cells. An increasing body of evidence suggests an interrelationship between processes responsive to nitrogen stress with cAMP-dependent PKA and the TOR kinase complex acting as key regulators of autophagy, pseudohyphal growth, and endocytosis. In this review, we will summarize our current understanding of the regulatory events controlling these processes. In particular, we explore the interplay between autophagy, polarized pseudohyphal growth, and to a lesser extent endocytosis, and posit that the integrated response of these processes in yeast is a critical point for further laboratory experimentation as a model of cellular responses to nitrogen limitation throughout the Eukaryota.
|
|
Received: 14 May 2012; in revised form: 6 June 2012 / Accepted: 15 June 2012 / Published: 6 July 2012
Show/Hide Abstract
| Download PDF Full-text (405 KB) | Download XML Full-text
Abstract: Autophagy is an intracellular degradation process responsible for the delivery of cellular material to the lysosomes. One of the key mechanisms for control of autophagy is the modulation of the interaction between the autophagic protein Beclin 1 and the members of the anti-apoptotic Bcl-2 family (e.g., Bcl-2, Bcl-XL and Mcl-1). This binding is regulated by a variety of proteins and compounds that are able to enhance or inhibit the Bcl-2/Beclin 1 interaction in order to repress or activate autophagy, respectively. In this review we will focus on this interaction and discuss its characteristics, relevance and regulation.
|
|
Received: 4 May 2012; in revised form: 18 June 2012 / Accepted: 13 July 2012 / Published: 26 July 2012
Show/Hide Abstract
| Download PDF Full-text (352 KB) | Download XML Full-text
Abstract: Skeletal muscles are the agent of motion and one of the most important tissues responsible for the control of metabolism. The maintenance of muscle homeostasis is finely regulated by the balance between catabolic and anabolic process. Macroautophagy (or autophagy) is a catabolic process that provides the degradation of protein aggregation and damaged organelles through the fusion between autophagosomes and lysosomes. Proper regulation of the autophagy flux is fundamental for the homeostasis of skeletal muscles during physiological situations and in response to stress. Defective as well as excessive autophagy is harmful for muscle health and has a pathogenic role in several forms of muscle diseases. This review will focus on the role of autophagy in muscle homeostasis and diseases.
|
|
Received: 28 June 2012; in revised form: 14 July 2012 / Accepted: 16 July 2012 / Published: 27 July 2012
Show/Hide Abstract
| Download PDF Full-text (1706 KB) | Download XML Full-text
Abstract: Autophagy is a ubiquitous eukaryotic process that also occurs in trypanosomatid parasites, protist organisms belonging to the supergroup Excavata, distinct from the supergroup Opistokontha that includes mammals and fungi. Half of the known yeast and mammalian AuTophaGy (ATG) proteins were detected in trypanosomatids, although with low sequence conservation. Trypanosomatids such as Trypanosoma brucei, Trypanosoma cruzi and Leishmania spp. are responsible for serious tropical diseases in humans. The parasites are transmitted by insects and, consequently, have a complicated life cycle during which they undergo dramatic morphological and metabolic transformations to adapt to the different environments. Autophagy plays a major role during these transformations. Since inhibition of autophagy affects the transformation, survival and/or virulence of the parasites, the ATGs offer promise for development of drugs against tropical diseases. Furthermore, various trypanocidal drugs have been shown to trigger autophagy-like processes in the parasites. It is inferred that autophagy is used by the parasites in an—not always successful—attempt to cope with the stress caused by the toxic compounds.
|
|
Received: 7 May 2012; in revised form: 22 June 2012 / Accepted: 13 July 2012 / Published: 27 July 2012
Show/Hide Abstract
| Download PDF Full-text (409 KB) | Download XML Full-text
Abstract: Autophagy is an evolutionarily conserved process that contributes to maintain cell homeostasis. Although it is strongly regulated by many extracellular factors, induction of autophagy is mainly produced by starvation of nutrients. In mammalian cells, the regulation of autophagy by amino acids, and also by the hormone insulin, has been extensively investigated, but knowledge about the effects of other autophagy regulators, including another nutrient, glucose, is more limited. Here we will focus on the signalling pathways by which environmental glucose directly, i.e., independently of insulin and glucagon, regulates autophagy in mammalian cells, but we will also briefly mention some data in yeast. Although glucose deprivation mainly induces autophagy via AMPK activation and the subsequent inhibition of mTORC1, we will also comment other signalling pathways, as well as evidences indicating that, under certain conditions, autophagy can be activated by glucose. A better understanding on how glucose regulates autophagy not only will expand our basic knowledge of this important cell process, but it will be also relevant to understand common human disorders, such as cancer and diabetes, in which glucose levels play an important role.
 |
|
Received: 13 June 2012; in revised form: 21 July 2012 / Accepted: 23 July 2012 / Published: 30 July 2012
Show/Hide Abstract
| Download PDF Full-text (600 KB) | Download XML Full-text
Abstract: Autophagy is an intracellular degradative process with a number of roles, one of which can be the protection of eukaryotic cells from invading microbes. Microtubule-associated protein light-chain 3 (LC3) is a key autophagy-related protein that is recruited to the double-membrane autophagosome responsible for sequestering material intended for delivery to lysosomes. GFP-LC3 is widely used as a marker of autophagosome formation as denoted by the formation of green puncta when viewed by fluorescence microscopy. Recently, it has been demonstrated that LC3 can be recruited to other membranes including single-membrane phagosomes, in a process termed LC3-associated phagocytosis (LAP). Thus, the observation of green puncta in cells can no longer, by itself, be taken as evidence of autophagy. This review will clarify those features of LAP which serve to distinguish it from autophagy and that make connections with host autophagic responses in terms of infection by microbial pathogens. More specifically, it will refer to concurrent studies of the mechanism by which LAP is triggered in comparison to autophagy.
|
|
Received: 9 May 2012; in revised form: 28 June 2012 / Accepted: 18 July 2012 / Published: 2 August 2012
Show/Hide Abstract
| Download PDF Full-text (1037 KB) | Download XML Full-text
Abstract: Autophagy is an evolutionarily conserved catabolic process by which cells degrade their own components through the lysosomal machinery. In physiological conditions, the mechanism is tightly regulated and contributes to maintain a balance between synthesis and degradation in cells undergoing intense metabolic activities. Autophagy is associated with major tissue remodeling processes occurring through the embryonic, fetal and early postnatal periods of vertebrates. Here we survey current information implicating autophagy in cellular death, proliferation or differentiation in developing vertebrates. In developing systems, activation of the autophagic machinery could promote different outcomes depending on the cellular context. Autophagy is thus an extraordinary tool for the developing organs and tissues.
|
|
Received: 2 May 2012; in revised form: 7 June 2012 / Accepted: 17 July 2012 / Published: 2 August 2012
Show/Hide Abstract
| Download PDF Full-text (268 KB) | Download XML Full-text
Abstract: Macroautophagy is a non-selective, bulk degradation process conserved in eukaryotes. Response to starvation stress and/or regulation of nutrient breakdown/utilization is the major intracellular function of macroautophagy. Recent studies have revealed requirement for autophagy in diverse functions such as nutrient homeostasis, organelle degradation and programmed cell death in filamentous fungal pathogens, for proper morphogenesis and differentiation during critical steps of infection. In this review, we aim to summarize the physiological functions of autophagy in fungal virulence, with an emphasis on nutrient homeostasis in opportunistic human fungal pathogens and in the rice-blast fungus, Magnaporthe oryzae. We briefly summarize the role of autophagy on the host side: for resistance to, or subversion by, the pathogens.
|
|
Received: 15 June 2012; in revised form: 9 July 2012 / Accepted: 19 July 2012 / Published: 3 August 2012
Show/Hide Abstract
| Download PDF Full-text (582 KB) | Download XML Full-text
Abstract: Autophagy is an important cellular program with a “double face” role, since it promotes either cell survival or cell death, also in cancer therapies. Its survival role occurs by recycling cell components during starvation or removing stressed organelles; when damage becomes extensive, autophagy provides another programmed cell death pathway, known as Autophagic Cell Death (ACD). The induction of autophagy is a common outcome in PhotoDynamic Therapy (PDT), a two-step process involving the irradiation of photosensitizer (PS)-loaded cancer cells. Upon tissue oxygen interaction, PS provokes immediate and direct Reactive Oxygen Species (ROS)-induced damage to Endoplasmic Reticulum (ER), mitochondria, plasma membrane, and/or lysosomes. The main biological effects carried out in cancer PDT are direct cytotoxicity to tumor cells, vasculature damage and induction of inflammatory reactions stimulating immunological responses. The question about the role of autophagy in PDT and its putative immunological impact is hotly controversial and largely studied in recent times. This review deals with the induction of autophagy in PDT protocols and its dual role, also considering its interrelationship with apoptosis, the preferential cell death program triggered in the photodynamic process.
 |
|
Received: 18 June 2012; in revised form: 20 July 2012 / Accepted: 23 July 2012 / Published: 3 August 2012
Show/Hide Abstract
| Download PDF Full-text (669 KB) | Download XML Full-text
Abstract: (Macro)-autophagy is a homeostatic process by which eukaryotic cells dispose of protein aggregates and damaged organelles. Autophagy is also used to degrade micro-organisms that invade intracellularly in a process termed xenophagy. Genome-wide association scans have recently identified autophagy genes as conferring susceptibility to Crohn’s disease (CD), one of the chronic inflammatory bowel diseases, with evidence suggesting that CD arises from a defective innate immune response to enteric bacteria. Here we review the emerging role of autophagy in CD, with particular focus on xenophagy and enteric E. coli strains with an adherent and invasive phenotype that have been consistently isolated from CD patients with ileal disease.
|
|
Received: 14 June 2012; in revised form: 28 June 2012 / Accepted: 30 July 2012 / Published: 13 August 2012
Show/Hide Abstract
| Download PDF Full-text (1173 KB) | Download XML Full-text | 
Abstract: Autophagy is a housekeeping survival mechanism with a protective function against stress conditions. However, when stress severity or duration increases, it may promote cell death. Paradoxically, autophagy favors cancer development, since cancer cells could enhance their proliferation potential (thus becoming able to resist anticancer therapy) thanks to the energetic supply provided by organelle degradation typically driven by autophagy following a stepwise pathway. The main actors of the autophagic machinery as well as the features shared with apoptosis will be described. Special attention will be paid to the effects of autophagy manipulation.
|
|
Received: 7 May 2012; in revised form: 4 July 2012 / Accepted: 1 August 2012 / Published: 21 August 2012
Show/Hide Abstract
| Download PDF Full-text (435 KB) | Download XML Full-text
Abstract: The intestine lies at the interface between the organism and its environment and responds to infection/inflammation in a multi-leveled manner, potentially leading to chronic inflammatory pathologies and cancer formation. Indeed, the immune response at the intestinal epithelium has been found to be involved in the origin and development of colorectal cancer, which is the third most commonly diagnosed neoplastic disease. Among the mechanisms induced upon inflammation, autophagy appears as a defensive strategy for the clearance of invading microbes and intracellular waste components. Autophagy has also been found to play an important role in colorectal cancer, where it seems to have a pro-survival or pro-death function depending on the stage of the neoplastic process. In this paper we discuss the dual role of autophagy in colorectal cancer and review evidence showing that modulation of autophagy affects the immune response and cancer biology. The study of key players involved in autophagy might contribute to the design of new approaches for colorectal cancer, consisting in combined therapies capable of modifying cancer-specific metabolism rather than simply evoking a generic apoptotic and/or autophagic response, thus enhancing the efficacy of currently used drugs and treatments.
|
|
Received: 17 June 2012; in revised form: 11 August 2012 / Accepted: 16 August 2012 / Published: 23 August 2012
Show/Hide Abstract
| Download PDF Full-text (697 KB) | Download XML Full-text
Abstract: All the therapeutic strategies for treating cancers aim at killing the cancer cells via apoptosis (programmed cell death type I). Defective apoptosis endow tumor cells with survival. The cell can respond to such defects with autophagy. Autophagy is a cellular process by which cytoplasmic material is either degraded to maintain homeostasis or recycled for energy and nutrients in starvation. A plethora of evidence has shown that the role of autophagy in tumors is complex. A lot of effort is needed to underline the functional status of autophagy in tumor progression and treatment, and elucidate how to tweak autophagy to treat cancer. Furthermore, during the treatment of cancer, the limitation for the cure rate and survival is the phenomenon of multi drug resistance (MDR). The development of MDR is an intricate process that could be regulated by drug transporters, enzymes, anti-apoptotic genes or DNA repair mechanisms. Reports have shown that autophagy has a dual role in MDR. Furthermore, it has been reported that activation of a death pathway may overcome MDR, thus pointing the importance of other death pathways to regulate tumor cell progression and growth. Therefore, in this review we will discuss the role of autophagy in MDR tumors and a possible link amongst these phenomena.
|
|
Received: 19 July 2012; in revised form: 10 August 2012 / Accepted: 14 August 2012 / Published: 27 August 2012
Show/Hide Abstract
| Download PDF Full-text (456 KB) | Download XML Full-text
Abstract: In recent years, research on the autophagic process has greatly increased, invading the fields of biology and medicine. Several markers of the autophagic process have been discovered and various strategies have been reported studying this molecular process in different biological systems in both physiological and stress conditions. Furthermore, mechanisms of metalloid- or heavy metal-induced toxicity continue to be of interest given the ubiquitous nature and distribution of these contaminants in the environment where they often play the role of pollutants of numerous organisms. The aim of this review is a critical analysis and correlation of knowledge of autophagic mechanisms studied under stress for the most common arsenic (As) and cadmium (Cd) compounds. In this review we report data obtained in different experimental models for each compound, highlighting similarities and/or differences in the activation of autophagic processes. A more detailed discussion will concern the activation of autophagy in Cd-exposed sea urchin embryo since it is a suitable model system that is very sensitive to environmental stress, and Cd is one of the most studied heavy metal inductors of stress and modulator of different factors such as: protein kinase and phosphatase, caspases, mitochondria, heat shock proteins, metallothioneins, transcription factors, reactive oxygen species, apoptosis and autophagy.
|
|
Received: 1 July 2012; in revised form: 11 August 2012 / Accepted: 21 August 2012 / Published: 27 August 2012
Show/Hide Abstract
| Download PDF Full-text (299 KB) | Download XML Full-text
Abstract: Viruses commandeer regulatory pathways of their hosts to optimize their success as cellular parasites. The human tumor viruses, Epstein-Barr Virus (EBV), Kaposi’s Sarcoma Herpesvirus (KSHV), Hepatitis B Virus (HBV), and Hepatitis C Virus (HCV) all affect autophagy for their own ends. EBV and KSHV regulate it during latent infections, a phase when no progeny virus is produced, while HBV and HCV use autophagy to promote their productive infections. Here we shall compare and contrast how these human tumor viruses regulate autophagy and what they gain by the appropriation of this cellular pathway.
|
|
Received: 30 June 2012; in revised form: 3 August 2012 / Accepted: 18 September 2012 / Published: 15 October 2012
Show/Hide Abstract
| Download PDF Full-text (221 KB) | Download XML Full-text
Abstract: 14-3-3 proteins are implicated in the regulation of proteins involved in a variety of signaling pathways. 14-3-3-dependent protein regulation occurs through phosphorylation-dependent binding that results, in many cases, in the release of survival signals in cells. Autophagy is a cell digestion process that contributes to overcoming nutrient deprivation and is initiated under stress conditions. However, whether autophagy is a cell survival or cell death mechanism remains under discussion and may depend on context. Nevertheless, autophagy is a cellular process that determines cell fate and is tightly regulated by different signaling pathways, some of which, for example MAPK, PI3K and mTOR, are tightly regulated by 14-3-3 proteins. It is therefore important to understand the role of 14-3-3 protein in modulating the autophagic process. Within this context, direct binding of 14-3-3 to mTOR regulatory proteins, such as TSC2 and PRAS40, connects 14-3-3 with autophagy regulatory processes. In addition, 14-3-3 binding to human vacuolar protein sorting 34 (hVps34), a class III phosphatidylinositol-3-kinase (PI3KC3), indicates the involvement of 14-3-3 proteins in regulating autophagosome formation. hVps34 is involved in vesicle trafficking processes such as autophagy, and its activation is needed for initiation of autophagy. Chromatography and overlay techniques suggest that hVps34 directly interacts with 14-3-3 proteins under physiological conditions, thereby maintaining hVps34 in an inactive state. In contrast, nutrient starvation promotes dissociation of the 14-3-3–hVps34 complex, thereby enhancing hVps34 lipid kinase activity. Thus, 14-3-3 proteins are regulators of autophagy through regulating key components of the autophagic machinery. This review summarizes the role of 14-3-3 protein in the control of target proteins involved in regulating the master switches of autophagy.
|
|
Received: 17 September 2012; in revised form: 31 October 2012 / Accepted: 7 November 2012 / Published: 25 January 2013
Show/Hide Abstract
| Download PDF Full-text (878 KB) | Download XML Full-text
Abstract: Viruses have played an important role in human evolution and have evolved diverse strategies to co-exist with their hosts. As obligate intracellular pathogens, viruses exploit and manipulate different host cell processes, including cellular trafficking, metabolism and immunity-related functions, for their own survival. In this article, we review evidence for how autophagy, a highly conserved cellular degradative pathway, serves either as an antiviral defense mechanism or, alternatively, as a pro-viral process during virus infection. Furthermore, we highlight recent reports concerning the role of selective autophagy in virus infection and how viruses manipulate autophagy to evade lysosomal capture and degradation.
|
Last update: 3 January 2013
