Hayat Autophagy: Cancer, Other Pathologies, Inflammation, Immunity, Infection, and Aging

Volume 6- Regulation of Autophagy and Selective Autophagy
1. Auflage 2014
ISBN: 978-0-12-801053-2
Verlag: Elsevier Science & Techn.
Format: EPUB
Kopierschutz: Adobe DRM (»Systemvoraussetzungen)

E-Book, Englisch, 338 Seiten

Volume 6 provides coverage of the mechanisms of regulation of autophagy; intracellular pathogen use of the autophagy mechanism; the role of autophagy in host immunity; and selective autophagy. Attention is given to a number of mechanistic advances in the understanding of regulation, particularly the importance of nutrient availability; microRNAs; and cross-talk with other protein degradation pathways. Intracellular pathogen repurposing of autophagy for pathogenic benefit is also provided, with coverage of Herpesvirus protein modulation of autophagy; the varicella-zoster virus and the maintenance of homeostasis; and the relationship between autophagy and the hepatitis b virus. The significance of autophagy in host defense is elucidated, providing a specific focus on facilitation of antigen presentation; participation in thymic development; and the sharing of regulatory nodes with innate immunity. Selective autophagy for the degradation of mitochondria and endocytosed gap junctions are also explored. This book is an asset to newcomers as a concise overview of the regulation of autophagy, its role in host defense and immunity, and selective autophagy, while serving as an excellent reference for more experienced scientists and clinicians looking to update their knowledge.  Volumes in the Series

Autoren/Hrsg.

Hayat, M. A.

Inhaltsverzeichnis

1;Front Cover;1
2;Autophagy: Cancer, Other Pathologies, Inflammation, Immunity, Infection, and Aging;4
3;Copyright Page;5
4;Dedication;6
5;Mitophagy and Biogenesis;8
6;Autophagy and Cancer;12
7;Contents;14
8;Foreword;18
9;Preface;20
10;Contributors;24
11;Abbreviations and Glossary;26
12;Autophagy: Volume 1 – Contributions;36
13;Autophagy: Volume 2 – Contributions;38
14;Autophagy: Volume 3 – Contributions;40
15;Autophagy: Volume 4 – Contributions;42
16;Autophagy: Volume 5 – Contributions;44
17;1 Introduction to Autophagy: Cancer, Other Pathologies, Inflammation, Immunity, Infection, and Aging, Volume 6;46
17.1;Introduction;47
17.2;Specific Functions of Autophagy (A Summary);49
17.3;Autophagy in Normal Mammalian Cells;49
17.4;Endoplasmic Reticulum Stress and Autophagy;50
17.5;Major Types of Autophagies;52
17.5.1;Macroautophagy (Autophagy);52
17.5.2;Microautophagy;52
17.5.3;Chaperone-Mediated Autophagy;52
17.6;Autophagosome Formation;53
17.7;Autophagic Lysosome Reformation;54
17.8;Autophagic Proteins;55
17.8.1;Abnormal Proteins;56
17.8.2;Protein Degradation Systems;57
17.8.3;Beclin 1;58
17.8.4;Non-Autophagic Functions of Autophagy-Related Proteins;58
17.8.5;Microtubule-Associated Protein Light Chain 3;59
17.9;Monitoring Autophagy;60
17.10;Reactive Oxygen Species (ROS);60
17.11;Mammalian Target of Rapamycin (mTOR);61
17.12;Role of Autophagy in Tumorigenesis and Cancer;62
17.13;Role of Autophagy in Immunity;64
17.14;Autophagy and Senescence;65
17.15;Role of Autophagy in Viral Defense and Replication;66
17.16;Role of Autophagy in Intracellular Bacterial Infection;67
17.17;Role of Autophagy in Heart Disease;68
17.18;Role of Autophagy in Neurodegenerative Diseases;69
17.19;Cross-Talk between Autophagy and Apoptosis;71
17.20;Autophagy and Ubiquitination;74
17.21;Aggresome: Ubiquitin Proteasome and Autophagy Systems;75
17.22;Autophagy and Necroptosis;76
17.23;Mitochondrial Fusion and Fission;76
17.24;Selective Autophagies;77
17.24.1;Allophagy;78
17.24.2;Axonopathy (Neuronal Autophagy);79
17.24.3;Crinophagy;80
17.24.4;Glycophagy;80
17.24.4.1;Lipophagy;81
17.24.4.1.1;Role of Lipophagy in Alcohol-Induced Liver Disease;82
17.24.4.2;Mitophagy;83
17.24.4.3;Nucleophagy;84
17.24.5;Pexophagy;85
17.24.5.1;Reticulophagy;86
17.24.5.2;Ribophagy;87
17.24.5.3;Xenophagy;88
17.24.5.4;Zymophagy;88
17.25;References;89
18;I. Autophagy and Molecular Mechanisms;98
18.1;2 Regulation of Autophagy by Amino Acids;100
18.1.1;Introduction;101
18.1.2;Overview of the Insulin-Amino Acid-MTOR Signaling Pathway;101
18.1.3;Amino Acids, MTOR Signaling and the Regulation of Autophagy;104
18.1.3.1;Rag GTPases, v-ATPase, t-RNA Synthetases and Regulation of Autophagy;105
18.1.3.2;Glutamate Dehydrogenase and Regulation of Autophagy;106
18.1.3.3;Other Pathways Involved in the Amino Acid Regulation of Autophagy;107
18.1.3.4;Plasma Membrane Derived Signaling and Regulation of Amino Acid-Dependent Autophagy;108
18.1.4;Amino Acids, Beclin-1 and the Regulation of Autophagy;109
18.1.4.1;Beclin-1 Complexes and Autophagy;110
18.1.4.2;Regulation of the Activity of the Beclin-1 Complex during Starvation;110
18.1.5;Conclusion;111
18.1.6;References;112
18.2;3 Regulation of Autophagy by Amino Acid Starvation Involving Ca2+;114
18.2.1;Introduction;115
18.2.2;Regulation of Autophagy by Amino Acids;117
18.2.2.1;Inhibition of Autophagy by Amino Acids;117
18.2.2.2;Induction of Autophagy by Amino Acid Starvation;118
18.2.3;Ca2+-dependent Activation of Autophagy by Amino Acid Starvation;119
18.2.4;Ca2+/CaMKK-ß-dependent Autophagy and Energy;120
18.2.5;Conclusion;122
18.2.6;Acknowledgments;123
18.2.7;References;123
18.3;4 Regulation of Autophagy by microRNAs;126
18.3.1;Introduction;127
18.3.2;Molecular Mechanisms of Autophagy;127
18.3.2.1;Initiation and Formation of the Autophagosome;128
18.3.2.2;Elongation of the Autophagosome;129
18.3.2.3;Maturation and Fusion with the Lysosomes;130
18.3.3;Major Signaling Pathways Regulating Autophagy;130
18.3.3.1;mTOR Pathway;130
18.3.3.2;AKT/PKB and Growth Factors;131
18.3.3.3;FoxO Regulation of Autophagy;131
18.3.3.4;AMPK Pathway;131
18.3.3.5;Inositol Pathway;131
18.3.3.6;Stress-Responsive BECN1/BCL2 Complex;132
18.3.3.7;Hypoxia, ROS and Autophagy;132
18.3.3.8;P53 Pathway;132
18.3.4;Small Regulators: microRNAs, their Biogenesis and Biological Functions;133
18.3.4.1;microRNAs;133
18.3.4.2;microRNA Biogenesis;133
18.3.5;micrornas: Novel Regulators of Autophagy;135
18.3.5.1;miRNA Regulation of Signals Upstream to Autophagy Pathways;135
18.3.5.2;miRNA Regulation of Autophagosome Initiation and Formation;139
18.3.5.3;miRNA Regulation of the Autophagosome Elongation Step;140
18.3.5.4;miRNA Regulation of Vesicular Transport Events, Autophagosome Maturation and Fusion with Lysosomes;141
18.3.6;microRNA Regulation of Autophagy-Related Signaling Pathways;141
18.3.7;Conclusion;142
18.3.8;Acknowledgments;144
18.3.9;References;144
18.4;5 Mechanisms of Cross-Talk between Intracellular Protein Degradation Pathways;148
18.4.1;Introduction;149
18.4.2;The Ubiquitin-Proteasome System: Selective Degradation of Cytoplasmic Proteins;149
18.4.2.1;Ubiquitin-Dependent Protein Targeting;150
18.4.2.2;The Molecular Architecture of the Proteasome;151
18.4.3;The Three Branches of Autophagy: Diverse Regulation of Lysosome-Dependent Degradation;152
18.4.3.1;Macroautophagy;152
18.4.3.2;Chaperone-Mediated Autophagy;154
18.4.3.3;Microautophagy;154
18.4.4;Regulation of Intracellular Proteolysis by Cross-Talk Between Degradation Pathways;155
18.4.4.1;Interplay between Autophagy Pathways;155
18.4.4.2;Ubiquitin: A Small Protein with a Big Job;156
18.4.5;Functional Implications of Cross-Talk: Autophagy Can Compensate for Ups Impairment but Not Vice Versa;157
18.4.5.1;Macroautophagy Upregulation in Response to UPS Disruption;157
18.4.5.2;The UPS is Impaired upon Autophagy Deregulation;159
18.4.6;Insights into the Physiological Consequences of Perturbed Proteolysis: Focus on Aging;160
18.4.6.1;Contribution of Protein Homeostasis to Aging;160
18.4.6.2;Age-Associated Changes in the UPS;160
18.4.6.3;Age-Related Changes in Autophagy;161
18.4.6.4;Cross-Talk between the UPS and Autophagy in Aging and Age-Related Diseases;161
18.4.7;Conclusion;163
18.4.8;Acknowledgments;163
18.4.9;References;163
18.5;6 Cross-Talk between Autophagy and Apoptosis in Adipose Tissue: Role of Ghrelin;166
18.5.1;Introduction;167
18.5.2;Apoptosis and Autophagy in Adipose Tissue;168
18.5.2.1;Apoptosis Signaling Pathways;168
18.5.2.2;Adipocyte Apoptosis;169
18.5.2.3;Regulatory Elements of Autophagy;170
18.5.2.4;Autophagy in the Adipose Tissue;171
18.5.3;Role of Ghrelin in the Regulation of Apoptosis and Autophagy in Adipose Tissue;172
18.5.3.1;The Ghrelin System;172
18.5.3.2;Ghrelin as a Survival Factor in Adipose Tissue;173
18.5.3.3;Ghrelin and Autophagy;174
18.5.4;Discussion;174
18.5.5;Acknowledgments;175
18.5.6;References;175
19;II. Autophagy and Intracellular Pathogens;178
19.1;7 Intracellular Pathogen Invasion of the Host Cells: Role of a-Hemolysin-Induced Autophagy;180
19.1.1;Introduction;181
19.1.2;Staphylococcus Aureus;181
19.1.2.1;Staphylococcus aureus, a Pathogen with a Dual Lifestyle;181
19.1.2.2;Interaction of S. aureus with the Autophagic Pathway;182
19.1.3;The S. Aureus a-hemolysin, a Key Secreted Virulence Factor;185
19.1.3.1;Pore-Forming Toxin a-Hemolysin;185
19.1.3.2;ADAM 10, the Hla Receptor in Host Cells;186
19.1.3.3;Hla is Capable of Inducing an Autophagic Response;186
19.1.4;Discussion;187
19.1.5;References;188
19.2;8 Modulation of Autophagy by Herpesvirus Proteins;190
19.2.1;Introduction;191
19.2.2;Inhibition of Autophagy by Herpesvirus Proteins;192
19.2.2.1;Modulation of the Autophagy Signaling Pathways;193
19.2.2.2;Inhibition of the Beclin-1 Initiation Complex;195
19.2.2.3;Inhibition of the LC3 Conjugation Complex;197
19.2.2.4;Inhibition of the Maturation Complex;197
19.2.3;Autophagy Activation by Herpesviruses;198
19.2.3.1;Herpesviridae Proteins that Activate Autophagy;199
19.2.3.2;Activation of Autophagy by Viral Nucleic Acids;200
19.2.4;Conclusion;201
19.2.5;Acknowledgments;201
19.2.6;References;201
19.3;9 Autophagy Induced by Varicella-Zoster Virus and the Maintenance of Cellular Homeostasis;204
19.3.1;Introduction;205
19.3.2;Varicella-Zoster Virus;205
19.3.3;The Disease Varicella;206
19.3.4;Characteristic Exanthems of Varicella and Herpes Zoster;206
19.3.4.1;Varicella Exanthem;206
19.3.4.2;Herpes Zoster Dermatomal Exanthem;207
19.3.5;Autophagy and its Visualization by Confocal Microscopy;207
19.3.6;Autophagosomes in the Exanthems of Varicella and Herpes Zoster;208
19.3.7;Evidence for ER Stress and Unfolded Protein Response;210
19.3.8;Acknowledgments;211
19.3.9;References;211
19.4;10 Autophagy and Hepatitis B Virus;214
19.4.1;Introduction;215
19.4.2;The HBV Life Cycle;215
19.4.3;Mechanism of HBV-Induced Autophagy;217
19.4.4;Autophagy on HBV Replication;218
19.4.5;Autophagy and HBV-Induced Hepatocarcinogenesis;219
19.4.6;Conclusion;220
19.4.7;References;220
20;III. Autophagy and Immunity;222
20.1;11 Toll-Like Receptors Serve as Activators for Autophagy in Macrophages Helping to Facilitate Innate Immunity;224
20.1.1;Introduction;225
20.1.2;Toll-Like Receptors;226
20.1.3;Autophagy;227
20.1.3.1;Initial Reports that Linked Autophagy to the Clearance of Intracellular Pathogens;228
20.1.4;TLR-Induced Autophagy;229
20.1.5;Discussion;232
20.1.6;Acknowledgments;233
20.1.7;References;233
20.2;12 Autophagy in Antigen Processing for MHC Presentation to T Cells;236
20.2.1;Introduction;237
20.2.2;Cytosolic Antigen Presentation on MHC Class II Molecules;238
20.2.3;Autophagy Regulation of Phagocytosis;240
20.2.4;Antigen Packaging for Cross-Presentation Via Macroautophagy;241
20.2.5;Regulation of MHC Class I Antigen Processing by Macroautophagy;241
20.2.6;Autophagy and Autoimmunity;242
20.2.7;Discussion;242
20.2.8;Acknowledgments;243
20.2.9;References;243
20.3;13 Autophagy Controls the Production and Secretion of IL-1ß: Underlying Mechanisms;246
20.3.1;Introduction;247
20.3.2;Interleukin-1ß: Biological Functions and Regulation;247
20.3.3;Role of Autophagy in Interleukin-1ß Secretion;248
20.3.3.1;Autophagy Controls Inflammasome Activation;249
20.3.3.2;IL-1ß and Inflammasome Components are Degraded in Autophagosomes;249
20.3.4;Autophagy and Innate Th17 Immune Responses;250
20.3.5;Autophagy and Inflammatory Diseases;251
20.3.6;Conclusion;252
20.3.7;References;253
20.4;14 Role of Autophagy in P2X7 Receptor-Mediated Maturation and Unconventional Secretion of IL-1ß in Microglia;256
20.4.1;Introduction;257
20.4.2;Role of Lysosomes in the Maturation of IL-1ß;258
20.4.2.1;Conventional and Secretory Lysosomes;258
20.4.2.2;Involvement of Lysosomal Enzymes in the Processing of Pro-IL-1ß;258
20.4.3;Autophagy Might Regulate the Maturation and Secretion of IL-1ß;260
20.4.3.1;Role of Autophagy in the Innate Immune System;260
20.4.3.2;Control of the Maturation and Secretion of IL-1ß by Autophagy;260
20.4.4;P2X7R-Mediated Maturation and Unconventional Secretion of IL-1ß;262
20.4.4.1;Functional Expression of P2X7R in Microglia;262
20.4.4.2;P2X7R-Mediated Unconventional Secretion Pathway for mIL-1ß;263
20.4.4.3;P2X7R-Mediated Regulation of Autophagy;264
20.4.4.4;Role of Autophagy in the P2X7R-Mediated Maturation and Secretion of IL-1ß;265
20.4.4.5;P2X7R-Mediated Secretion of IL-1ß as a Therapeutic Target in Neurodegenerative Disease;265
20.4.5;Acknowledgments;266
20.4.6;References;266
20.5;15 Autophagy Restricts Interleukin-1ß Signaling via Regulation of P62 Stability;268
20.5.1;Introduction;269
20.5.1.1;Role of Atg16L1 in TLR Signaling;270
20.5.1.2;Regulation of p62 Stability and IL-1ß Signal Transduction by Autophagy;270
20.5.1.3;Regulation of P62 Ubiquitination by Atg16L1;271
20.5.2;Discussion;271
20.5.3;Acknowledgments;273
20.5.4;References;273
20.6;16 Roles of Autophagy in the Thymic Epithelium;276
20.6.1;Introduction;277
20.6.1.1;Thymic Epithelium;277
20.6.1.2;Autophagy;278
20.6.2;Evidence for Autophagy in the Thymic Epithelium;279
20.6.3;Evaluation of Epithelial Autophagy in T Cell Selection;281
20.6.3.1;Implication of Autophagy in Delivering Antigens to the MHC Class II Compartment;281
20.6.3.2;Thymus Grafts from Autophagy-Deficient Embryos;281
20.6.3.3;Investigation of Autophagy in Medullary Epithelial Cells;282
20.6.3.4;Deletion of Autophagy-Related Genes in Thymic Epithelial Cells;283
20.6.4;Conclusion;284
20.6.5;References;284
21;IV. Autophagy: General Applications;286
21.1;17 The Role of Autophagy Receptors in Mitophagy;288
21.1.1;Introduction;289
21.1.1.1;Mitochondrial Dynamics;289
21.1.1.2;General Autophagy;290
21.1.1.3;Selective Autophagy;291
21.1.2;Autophagy Receptors;292
21.1.2.1;p62 and NBR1;292
21.1.2.2;NDP52 and Optineurin;295
21.1.3;Mitophagy;295
21.1.3.1;Removal of Damaged Mitochondria;296
21.1.3.2;Mitophagy Receptors: Atg32, BNIP3 and BNIP3L/NIX;297
21.1.4;Discussion;299
21.1.5;Acknowledgments;299
21.1.6;References;299
21.2;18 The Role of Parkin and PINK1 in Mitochondrial Quality Control;302
21.2.1;Introduction;303
21.2.2;Parkinson’s Disease and Mitochondrial Dysfunction;304
21.2.3;Parkin and PINK1 Mutant Flies;305
21.2.4;Stabilization of PINK1 on Mitochondria;306
21.2.5;PINK1 Activity on the Mitochondria;309
21.2.6;Parkin: A PD-Associated E3-Ubiquitin Ligase;309
21.2.7;PINK1-Mediated Recruitment of Parkin onto Mitochondria;311
21.2.8;Parkin-Mediated Ubiquitination of Mitochondrial Proteins;311
21.2.9;Parkin/PINK1-Mediated Mitophagy;313
21.2.10;Mitophagy and Neurons;313
21.2.11;Discussion;314
21.2.12;References;315
21.3;19 Autophagy Degrades Endocytosed Gap Junctions;318
21.3.1;Introduction;319
21.3.1.1;Gap Junction Structure and Function;319
21.3.2;Results;320
21.3.2.1;Gap Junction Endocytosis Generates Cytoplasmic Double-Membrane Vesicles;320
21.3.2.2;Endocytosed Gap Junctions are Degraded by Autophagy;322
21.3.2.3;Structural Elements Warrant the Autophagic Degradation of Endocytosed Gap Junctions;323
21.3.2.4;Potential Other Degradation Pathways for Endocytosed Gap Junctions;324
21.3.2.5;Signals that Prime Gap Junctions for Endocytosis and Direct them to Autophagic Degradation;325
21.3.3;Discussion;326
21.3.4;Conclusion;327
21.3.5;Acknowledgments;327
21.3.6;References;328
22;Index;332

Leseproben

Preface
M.A. Hayat It is becoming clear that cancer is an exceedingly complex molecular network, consisting of tumor cells at different stages of differentiation and noncancerous cells from the tumor microenvironment, both of which play a role in sustaining cancer progression. The latter cells maintain a proinflammatory environment conducive to cancer progression through induction of angiogenesis and evasion of the innate immune system. Although induction of cancer cell death by apoptosis, autophagy and necroptosis has been the main system exploited as anticancer strategies, an understanding of the role of the alterations in cellular metabolism is necessary for the development of new, more effective anticancer therapies. For example, it is known that cancer cells switch towards aerobic glycolysis from mitochondrial oxidative phosphorylation. Autophagy, on the other hand, also possesses mechanisms that can promote cancer cell survival and growth of established tumors. Regarding cell survival, tumor cells themselves activate autophagy in response to cellular stress and/or increased metabolic demands related to rapid cell proliferation. Autophagy-related stress tolerance can enable cell survival by maintaining energy production that can lead to tumor growth and therapeutic resistance. Tumors are often subjected to metabolic stress due to insufficient vascularization. Under these circumstances, autophagy is induced and localized to these hypoxic regions where it supports survival of tumors. Aggressive tumors have increased metabolic demands because of their rapid proliferation and growth. Thus, such tumors show augmented dependency on autophagy for their survival. Defective autophagy causes abnormal mitochondria accumulation and reduced mitochondrial function in starvation, which is associated with reduced energy output. Because mitochondrial function is required for survival during starvation, autophagy supports cell survival. The recycling of intracellular constituents as a result of their degradation serves as an alternative energy source for tumor survival, especially during periods of metabolic stress. In this context, in tumor cells with defective apoptosis, autophagy allows prolonged survival of tumor cells. However, paradoxically, as mentioned above, autophagy is also associated with antitumorigenesis. Autophagy induced by cancer therapy can also be utilized by cancer cells to obtain nutrients for their growth and proliferation. Therefore, such treatments are counterproductive to therapeutic efficacy. This is the sixth volume of the seven-volume series, Autophagy: Cancer, Other Pathologies, Inflammation, Immunity, Infection and Aging. This series discusses in detail almost all aspects of the autophagy machinery in the context of cancer and certain other pathologies. Emphasis is placed on maintaining homeostasis during starvation or stress conditions by balancing the synthesis of cellular components and their degradation by autophagy. Both autophagy and ubiquitin-proteasome systems degrade damaged and superfluous proteins. Degradation of intracellular components through these catabolic pathways results in the liberation of basic building blocks required to maintain cellular energy and homeostasis. However, less than or more than optimal protein degradation can result in human pathologies. An attempt is made in this volume to include information on the extent to which various protein degradation pathways interact, collaborate or antagonize one another. It is known that conditions resulting in cellular stress (e.g., hypoxia, starvation, pathogen entry) activate autophagy, but dysregulation of autophagy at this stage might result in pathological states including cancer. MicroRNAs are non-protein-coding small RNAs that control levels of transcripts and proteins through post-transcriptional mechanisms. Current knowledge of microRNA regulation of autophagy is presented in this volume. Autophagy (macroautophagy) is strictly regulated and the second messenger Ca+2 regulates starvation-induced autophagy. Withdrawal of essential amino acids increases intracellular Ca+2, leading to the activation of adenosine monophosphate-activated protein kinase and the inhibition of the mTORC1, which eventually results in the enhanced formation of autophagosomes. The importance of this signaling pathway and other pathways (AMPK, AKT) within the autophagy signaling network is emphasized in this volume. Recent discoveries of autophagic receptors that recognize specific cellular cargo have opened a new chapter in the autophagy field. Receptors are indispensable for the initiation and finalization of specific cargo removal by autophagy. For example, BNIP3L/NIX mediates mitochondrial clearance, which is discussed in this volume. It is pointed out that, in the absence of such clearance, accumulation of ROS can severely damage the mitochondrial population within the neuron and ultimately cause apoptosis of the affected neurons. Mitochondrial dysfunction is implicated in Parkinson’s disease. Toll-like receptors (TLRs) play critical roles in host defense by recognizing specific molecular patterns from a wide variety of pathogens. In macrophages, TLR signaling induces autophagy, limiting the replication of intracellular pathogens. How TLRs activate autophagosome formation in macrophages and enhance immunity is discussed in this volume. Autophagy plays an important role during viral and bacterial infection. Autophagy can act either as a part of the immune defense system or as a pro-viral or pro-bacterial mechanism. In other words, although autophagy suppresses the replication of some viruses, it enhances the replication of others. Several examples of the latter viruses are discussed in this volume. For example, Herpes viridae family members encode autophagy-regulating proteins, which contribute to the host antiviral defenses, either by enhancing innate immunity or by helping antigen presentation. Herpes viruses have also evolved proteins that are able to inhibit this cellular mechanism. Positive or negative impact of autophagy on viral infection is explained in this volume. Another example of the role of a virus in inducing autophagy is varicella-zoster virus (VZV); this human herpes virus causes chickenpox. Infected cells show a large number of autophagosomes and an enlarged endoplasmic reticulum (ER) indicating its stress, which is a precursor to autophagy through the inositol requiring enzyme-1 pathway and PERK pathway. Hepatocellular ß virus (HBV) also activates the autophagic pathway while avoiding lysosomal, protein degradation. As in the case of VZV, ER stress also plays a positive role in HBV replication. The possible effect of autophagy on HBV-induced hepatocarcinogenesis is also included in this volume. Staphylococcus aureus pathogen not only induces an autophagic response in the host cell (localizing in LC3 decorated components), but also benefits from that state. Although inflammatory responses are essential for eradicating intracellular pathogens and tissue repair, they can be detrimental to the host when uncontrolled. Therefore, inflammation needs to be tightly controlled to prevent excessive inflammation and collateral damage. Cytokine IL-1ß (produced by microglia in the CNS) is one of the pro-inflammatory mediators. The pivotal role of autophagy in regulating the production and secretion of the IL-1 family members is explained in this volume. Atg6L1, an essential component of autophagy, suppresses pro-inflammatory signaling. Better understanding of the role of the autophagy-lysosomal pathway in the maturation and secretion of IL-1 should provide a new strategy for targeting inflammation in various pathological conditions. Excess adiposity contributes to the development of obesity-associated metabolic disturbances such as insulin resistance, type 2 diabetes, or metabolic syndrome. It is pointed out that imbalance between ghrelin (a gut-derived hormone) and tumor necrosis factor in states of insulin resistance may contribute to altered apoptosis and autophagy found in the adipose tissue of patients with type 2 diabetes. By bringing together a large number of experts (oncologists, physicians, medical research scientists and pathologists) in the field of autophagy, it is my hope that substantial progress will be made against terrible diseases that inflict humans. It is difficult for a single author to discuss effectively and comprehensively various aspects of an exceedingly complex process such as autophagy. Another advantage of involving more than one author is to present different points of view on various controversial aspects of the role of autophagy in health and disease. I hope these goals will be fulfilled in this and future volumes of this series. This volume was written by 46 contributors representing 11 countries. I am grateful to them for their promptness in accepting my suggestions. Their practical experience highlights the very high quality of their writings, which should build and further the endeavors of the readers in this important medical field. I respect and appreciate the hard work and exceptional insight into the role of autophagy in disease provided by these contributors. It is my hope that subsequent volumes of this series will join this volume in assisting in the more complete understanding of the complex process of autophagy and eventually in the development of therapeutic applications. There exists a tremendous urgent demand by the public and the scientific community to develop better treatments for major diseases. In the light of the human impact of these untreated diseases, government funding must give priority to researching cures over global military superiority. I am...