Special Issue "Autophagy"

Guest Editor
Dr. Anne Hamacher-Brady
Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ) and BioQuant, INF 267, 69120 Heidelberg, Germany
Website: http://ibios.dkfz.de/tbi/index.php?option=com_jresearch&view=member&task=show&id=93&Itemid=92
E-Mail: a.hamacher@dkfz.de
Phone: +49 6221 5451322
Interests: autophagy; programmed cell death; apoptosis; lysosomes; cell biology; cancer research; cardiovascular disease

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

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• autophagy
• autophagosomes
• lysosomes
• degradation
• ubiquitin
• p62
• mitophagy
• programmed cell death
• reactive oxygen species
• metabolism

Type of Paper: Review
Title: Autophagy and Cancer
Authors: Francesca Aredia¹, Luis Miguel Guamán Ortiz^1,2 and A. Ivana Scovassi¹
Affiliations: ¹ IGM-CNR, Pavia, Italy; E-Mail: scovassi@igm.cnr.it
² UTPL, Loja, Ecuador
Abstract: Autophagy is generally considered a survival mechanism with a protective function against stress conditions, including those generated by anticancer treatments; however, when stress severity or duration increases, it may promote cell death. Autophagy is critical for cancer development; in fact, 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. The main actors of the autophagic machinery will be described; the role of autophagy in cancer progression, as well as new anticancer strategies based on autophagy manipulation, will be discussed.

Type of Paper: Review
Title: hVps34 Binds 14-3-3ζ Which Controls the Autophagy Initiation Process
Author: Mercedes Pozuelo
Affiliation: Centro Andaluz de Biología Molecular y Medicina Regenerativa, Consejo Superior de Investigaciones Científicas, Sevilla, Spain; E-Mail: merce_pozo@yahoo.es
Abstract: The human vacuolar protein sorting 34 (hVps34), the class III phosphatidylinositol-3-kinase is implicated in vesicle-trafficking processes such as autophagy, and its activation is needed for autophagy initiation. Chromatography and overlay techniques suggest a direct interaction of hVps34 with 14-3-3ζ protein under physiological conditions. Meanwhile, autophagy induction promotes dissociation of 14-3-3/hVps34 complex and enhances the hVps34 lipid kinase activity. It as been previously described, 14-3-3 proteins promotes cell survival and regulates cell fate through protein interaction. Data shown suggest that 14-3-3ζ binds hVps34 and promotes inhibition of its lipid kinase activity under normal growth condition. Thus, 14-3-3ζ protein becomes a negative regulator of autophagy through regulation of a key component of the autophagy machinery.

Type of Paper: Review
Title: Autophagy and Multidrug Resistance
Author: Zhe-Sheng Chen
Affiliation: College of Pharmacy and Allied Health Professions, St. John's University, 8000 Utopia Parkway, Queens, New York, NY 11439, USA; E-Mail: chenz@stjohns.edu
Abstract: Autophagy is a lysosome-dependent degradation pathway that allows cells to recycle damaged or superfluous cytoplasmic content including proteins, organelles and lipids. As a consequence of autophagy, the cells generate metabolic precursors for macromolecular biosynthesis or ATP generation. Deficiencies in this pathway were associated to several pathological conditions, such as neurodegenerative and cardiac diseases, cancer and aging. The aim of this review is to summarize recent discoveries showing that autophagy also plays a role in multidrug resistance.  In addition, autophagy may also play a role in stem cells maintenance and cell differentiation processes.

Type of Paper: Review
Title: Regulation of Autophagy by Glucose
Authors: J. Félix Moruno Manchón, Eva Pérez-Jiménez and Erwin Knecht
Affiliations: Cell Biology Laboratory, Príncipe Felipe Research Centre. Av. Autopista del Saler 16, 46012-Valencia, Spain; E-Mail: knecht@cipf.es
Abstract: Autophagy is an evolutionarily conserved process that contributes to maintain cell homeostasis. Although it is strongly regulated by many factors, induction of autophagy is mainly produced by starvation of nutrients such as amino acids. The regulation of autophagy by amino acids, and also by insulin, has been extensively investigated, but knowledge about other autophagy regulators, including glucose, is more limited. Here we will center on the regulation of autophagy, and also of other proteolytic pathways, by glucose in higher organisms. Although glucose deprivation can induce autophagy by activation of AMPK and inhibition of mTOR, we will also comment other evidences indicating that the effects of glucose on autophagy can be cell type-dependent and that, under certain conditions, an increase in glucose induces autophagy. A better understanding on how glucose regulates autophagy will not only expand our basic knowledge of this important cell process, but it will be also relevant to understand common human disorders with alterations in glucose levels, such as cancer and diabetes.

Type of Paper: Review
Title: The Role of Autophagy in Crohn’s Disease
Authors: Paul Henderson and Craig Stevens
Affiliation: University of Edinburgh; E-Mail: Craig.Stevens@ed.ac.uk
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. This review summarises recent progress made in understanding the role of autophagy in CD, with focus on the enteric E.coli strains with an adherent and invasive phenotype that have been consistently isolated from CD patients with ileal disease.

Type of Paper: Review
Title: Macroautophagy and cell responses related to mitochondrial dysfunction, metabolism, cell differentiation and non conventional secretion of proteins
Authors: Stéphane Demine, Anaïs Wanet, Sébastien Michel, Patricia Renard and Thierry Arnould
Affiliation: URBC-NARILIS (Unité de Recherche en Biologie Cellulaire-Namur Research Institute for Life Sciences, University of Namur (FUNDP), 61, rue de Bruxelles, 5000 Namur, Belgium; E-Mail: thierry.arnould@fundp.ac.be
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 will discuss some of the 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 cell differentiation and unconventional protein secretion.

Type of Paper: Review
Title: Human Tumor Viruses and Autophagy
Authors: Zach Pratt and Bill Sugden
Affiliation: McArdle Laboratory for Cancer Research, the University of Wisconsin; E-Mail: sugden@oncology.wisc.edu
Abstract: Human tumor viruses commandeer regulatory pathways of their hosts in order to be successful cellular parasites. In particular, Epstein-Barr Virus (EBV), Kaposi’s Sarcoma Herpesvirus (KSHV), Hepatitis B Virus (HBV), and Hepatitis C Virus (HCV) affect autophagy for their own ends.  The herpesviruses, EBV and KSHV, regulate it during latent infections 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 this appropriation.

Type of Paper: Review
Title: Modulation of autophagy related processes by tumor viruses
Authors: Karl Munger and Hildegard Mack
Affiliations: Harvard Medical School, Brigham and Women's Hospital, 181 Longwood Ave, MCP861 Boston, MA 02115, USA; E-Mails: kmunger@rics.bwh.harvard.edu (K.M.); hmack@rics.bwh.harvard.edu (H.M.)
Abstract: Autophagy is an intracellular degradation pathway for long-lived proteins and organelles. This process is activated above basal levels upon internal or environmental stress and dysregulation of autophagy has been linked to various human diseases, including 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 signalling networks. Here, we summarize recent advances in research at the interface of autophagy and viral infection, paying special attention to tumor viruses.

Type of Paper: Review
Title: An Overview of Autophagy and Yeast Pseudohyphal Growth: Integration of Signaling Pathways During Nitrogen Stress
Authors: Qingxuan Song and Anuj Kumar
Affiliation: Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, MI 48109-1048, USA; E-Mail: anujk@lsi.umich.edu
Abstract: The budding yeast Saccharomyces cerevisiae responds to nutritional stress through the precisely regulated activities of numerous signaling pathways mediating autophagy and other conserved cellular processes. Autophagy has been studied intensely in yeast, where over 30 autophagyrelated genes have been identified. These studies have provided us with a relatively sound understanding of the molecular events that enable the formation of autophagic vesicles and their subsequent trafficking to the central yeast vacuole; however, much less is known regarding the regulatory mechanisms through which autophagy is integrated with other yeast stress responses. Nitrogen limitation initiates both 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 these processes, with cAMP-dependent PKA and the nutritional stress-responsive TOR kinase complex acting as key regulators of both autophagy and pseudohyphal growth. TORC1, in addition, has recently been implicated in the regulation of Npr1-mediated endocytosis, and several transport proteins required for pseudohyphal growth are putatively regulated by endocytosis-mediated protein turnover. In this review, we will summarize our current understanding of the regulatory events controlling autophagy and pseudohyphal growth, highlighting the molecular overlap between the signaling components that regulate these processes. We explore here 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 stress throughout the Eukaryota.

Type of Paper: Review
Title: Heavy metals as autophagy inducing agents
Author: Roberto Chiarelli and Maria Carmela Roccheri
Affiliation: Department of STEMBIO (Biologia Cellulare), University of Palermo, Viale  delle Scienze Ed 16, 90128 Palermo, Italy; E-Mail: maria.roccheri@unipa.it
Abstract: In recent years, research on the autophagic process is greatly increased invading the fields of biology and medicine. Several markers of autophagic process were discovered and various strategies have been reported for studying this molecular process in different biological systems both in physiological and stress condition. Furthermore, mechanisms of heavy metal-induced toxicity continue to be of interest given the ubiquitous nature of these contaminants, the distribution of them is ubiquitous on the environment and often they play the role of pollutants for 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 heavy metals. In this review we report data obtained in different experimental models for each metal, highlighting similarities and/or differences in the activation of autophagic processes. A more detailed discussion will concern the activation of autophagy in cadmium-exposed sea urchin embryo since it is a suitable model system very sensitive to environmental stress and cadmium is one of the most studied heavy metal inductor of stress, modulator of different factors such as: protein kinase and phosphatase, caspases, mitochondria, heat shock proteins, metallothioneins, transcription factors, reactive oxygen species, in addition to apoptosis and autophagy.

Type of Paper: Review
Title: Autophagy Contributes to the Death/Survival Balance in Cancer PhotoDynamic Therapy
Author: V. Inguscio, E. Panzarini and L. Dini
Affiliation: Department of Biological and Environmental Science and Technology (Di.S.Te.B.A.), University of Salento,  Italy; E-Mail: luciana.dini@unisalento.it
Abstract: Autophagy is an important cellular program with a “double face” role, since it promotes both cell survival or cell death, also in cancer therapies. Its survival role occurs for recycling cell components during starvation or for 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 ROS-induced damage to endoplasmic reticulum (ER), mitochondria, plasma membrane, and/or lysosomes. The main biological effects carry out in cancer PDT are direct cytotoxicity of tumour 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 is dealing 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.

Type of Paper: Review
Title: The selectivity and specificity of autophagy during development in Drosophila
Author: Ioannis P. Nezis 1,2,*
Affiliations: ¹ Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Montebello, N-0310 Oslo, Norway
² Department of Biochemistry, Institute for Cancer Research, Oslo University Hospital, Montebello, N-0310, Oslo, Norway; E-Mail: Ioannis.Nezis@rr-research.no
Abstract: Autophagy is a process of cellular self-degradation and is a major pathway for elimination of cytoplasmic material by the lysosomal machinery. 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 occurs in the cell in a random manner, there is growing evidence during the last years that sequestration and degradation of cellular material by autophagy can be selective. Given the role of autophagy and selective autophagy in several disease related processes such as tumorigenesis, neurodegeneration and infections, it is very important to understand the molecular mechanisms of selective autophagy, especially at the organismal level. Drosophila is an excellent genetically modifiable model organism exhibiting high conservation in the autophagic machinery. However, the mechanisms of selective autophagy in Drosophila are largely unexplored. The aim of this review is to summarize recent discoveries about the selectivity of autophagy in Drosophila.

Type of Paper: Review
Title: Autophagy During Vertebrate Development
Authors: María R. Aburto ^1,2, Juan M. Hurlé ³, Isabel Varela-Nieto ^1,2,4 and Marta Magariños ^1,2,5
Affiliations: ¹ Institute for Biomedical Research “Alberto Sols”, CSIC-UAM, Madrid, Spain
² Unit 761, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Madrid, Spain
³ Departamentos de Anatomía y Biología Celular and Fisiología y Farmacología, Universidad de Cantabria, Santander 39011, Spain; E-Mail: hurlej@unican.es;
⁴ IdiPAZ, Madrid, Spain; 5 Departamento de Biología, Universidad Autónoma de Madrid, Madrid, Spain
Abstract: Autophagy is a self-degradative process that regulates protein and organelle removal in a variety of tissues during development and early postnatal stages. Autophagy plays a dual role as a physiological cell death mechanism and as a survival key process during critical times of embryogenesis. Through cytoplasmic remodeling autophagy participates in cellular death, proliferation or differentiation. The activation of the autophagic machinery could promote both death and survival depending on the cellular context; autophagy is thus an extraordinary tool for the developing organs and tissues.  This review summarizes the key findings on the homeostatic functions of autophagy on development of vertebrate cells and tissues.

Type of Paper: Review
Title: Autophagy in Trypanosomatids
Authors: Ana Brennand, Eva Rico-Vidal and Paul A. M. Michels
Affiliation: Research Unit for Tropical Diseases, de Duve Institute, Université catholique de Louvain, Brussels, Belgium; E-Mail: paul.michels@uclouvain.be
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 ATG proteins were detected in trypanosomatids, although with low sequence conservation.  Trypanosomatids such as Trypanosoma brucei, T. 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 the tropical diseases.

Type of Paper: Review
Title: Role of Macroautophagy in Nutrient Homeostasis during Fungal Development and Pathogenesis
Authors: Yi Zhen Deng, Ziwei Qu and Naweed I. Naqvi
Affiliation: Temasek Life Sciences Laboratory, and Department of Biological Sciences, 1 Research Link, National University of Singapore, Singapore 117604, Singapore; E-Mail: naweed@tll.org.sg
Abstract: Macroautophagy is a nonselective, 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 a 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.