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
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
Front Cover 1
Autophagy: Cancer, Other Pathologies, Inflammation, Immunity, Infection, and Aging 4
Copyright Page 5
Dedication 6
Mitophagy and Biogenesis 8
Autophagy and Cancer 12
Contents 14
Foreword 18
Preface 20
Contributors 24
Abbreviations and Glossary 26
Autophagy: Volume 1 – Contributions 36
Autophagy: Volume 2 – Contributions 38
Autophagy: Volume 3 – Contributions 40
Autophagy: Volume 4 – Contributions 42
Autophagy: Volume 5 – Contributions 44
1 Introduction to Autophagy: Cancer, Other Pathologies, Inflammation, Immunity, Infection, and Aging, Volume 6 46
Introduction 47
Specific Functions of Autophagy (A Summary) 49
Autophagy in Normal Mammalian Cells 49
Endoplasmic Reticulum Stress and Autophagy 50
Major Types of Autophagies 52
Macroautophagy (Autophagy) 52
Microautophagy 52
Chaperone-Mediated Autophagy 52
Autophagosome Formation 53
Autophagic Lysosome Reformation 54
Autophagic Proteins 55
Abnormal Proteins 56
Protein Degradation Systems 57
Beclin 1 58
Non-Autophagic Functions of Autophagy-Related Proteins 58
Microtubule-Associated Protein Light Chain 3 59
Monitoring Autophagy 60
Reactive Oxygen Species (ROS) 60
Mammalian Target of Rapamycin (mTOR) 61
Role of Autophagy in Tumorigenesis and Cancer 62
Role of Autophagy in Immunity 64
Autophagy and Senescence 65
Role of Autophagy in Viral Defense and Replication 66
Role of Autophagy in Intracellular Bacterial Infection 67
Role of Autophagy in Heart Disease 68
Role of Autophagy in Neurodegenerative Diseases 69
Cross-Talk between Autophagy and Apoptosis 71
Autophagy and Ubiquitination 74
Aggresome: Ubiquitin Proteasome and Autophagy Systems 75
Autophagy and Necroptosis 76
Mitochondrial Fusion and Fission 76
Selective Autophagies 77
Allophagy 78
Axonopathy (Neuronal Autophagy) 79
Crinophagy 80
Glycophagy 80
Lipophagy 81
Role of Lipophagy in Alcohol-Induced Liver Disease 82
Mitophagy 83
Nucleophagy 84
Pexophagy 85
Reticulophagy 86
Ribophagy 87
Xenophagy 88
Zymophagy 88
References 89
I. Autophagy and Molecular Mechanisms 98
2 Regulation of Autophagy by Amino Acids 100
Introduction 101
Overview of the Insulin-Amino Acid-MTOR Signaling Pathway 101
Amino Acids, MTOR Signaling and the Regulation of Autophagy 104
Rag GTPases, v-ATPase, t-RNA Synthetases and Regulation of Autophagy 105
Glutamate Dehydrogenase and Regulation of Autophagy 106
Other Pathways Involved in the Amino Acid Regulation of Autophagy 107
Plasma Membrane Derived Signaling and Regulation of Amino Acid-Dependent Autophagy 108
Amino Acids, Beclin-1 and the Regulation of Autophagy 109
Beclin-1 Complexes and Autophagy 110
Regulation of the Activity of the Beclin-1 Complex during Starvation 110
Conclusion 111
References 112
3 Regulation of Autophagy by Amino Acid Starvation Involving Ca2+ 114
Introduction 115
Regulation of Autophagy by Amino Acids 117
Inhibition of Autophagy by Amino Acids 117
Induction of Autophagy by Amino Acid Starvation 118
Ca2+-dependent Activation of Autophagy by Amino Acid Starvation 119
Ca2+/CaMKK-ß-dependent Autophagy and Energy 120
Conclusion 122
Acknowledgments 123
References 123
4 Regulation of Autophagy by microRNAs 126
Introduction 127
Molecular Mechanisms of Autophagy 127
Initiation and Formation of the Autophagosome 128
Elongation of the Autophagosome 129
Maturation and Fusion with the Lysosomes 130
Major Signaling Pathways Regulating Autophagy 130
mTOR Pathway 130
AKT/PKB and Growth Factors 131
FoxO Regulation of Autophagy 131
AMPK Pathway 131
Inositol Pathway 131
Stress-Responsive BECN1/BCL2 Complex 132
Hypoxia, ROS and Autophagy 132
P53 Pathway 132
Small Regulators: microRNAs, their Biogenesis and Biological Functions 133
microRNAs 133
microRNA Biogenesis 133
micrornas: Novel Regulators of Autophagy 135
miRNA Regulation of Signals Upstream to Autophagy Pathways 135
miRNA Regulation of Autophagosome Initiation and Formation 139
miRNA Regulation of the Autophagosome Elongation Step 140
miRNA Regulation of Vesicular Transport Events, Autophagosome Maturation and Fusion with Lysosomes 141
microRNA Regulation of Autophagy-Related Signaling Pathways 141
Conclusion 142
Acknowledgments 144
References 144
5 Mechanisms of Cross-Talk between Intracellular Protein Degradation Pathways 148
Introduction 149
The Ubiquitin-Proteasome System: Selective Degradation of Cytoplasmic Proteins 149
Ubiquitin-Dependent Protein Targeting 150
The Molecular Architecture of the Proteasome 151
The Three Branches of Autophagy: Diverse Regulation of Lysosome-Dependent Degradation 152
Macroautophagy 152
Chaperone-Mediated Autophagy 154
Microautophagy 154
Regulation of Intracellular Proteolysis by Cross-Talk Between Degradation Pathways 155
Interplay between Autophagy Pathways 155
Ubiquitin: A Small Protein with a Big Job 156
Functional Implications of Cross-Talk: Autophagy Can Compensate for Ups Impairment but Not Vice Versa 157
Macroautophagy Upregulation in Response to UPS Disruption 157
The UPS is Impaired upon Autophagy Deregulation 159
Insights into the Physiological Consequences of Perturbed Proteolysis: Focus on Aging 160
Contribution of Protein Homeostasis to Aging 160
Age-Associated Changes in the UPS 160
Age-Related Changes in Autophagy 161
Cross-Talk between the UPS and Autophagy in Aging and Age-Related Diseases 161
Conclusion 163
Acknowledgments 163
References 163
6 Cross-Talk between Autophagy and Apoptosis in Adipose Tissue: Role of Ghrelin 166
Introduction 167
Apoptosis and Autophagy in Adipose Tissue 168
Apoptosis Signaling Pathways 168
Adipocyte Apoptosis 169
Regulatory Elements of Autophagy 170
Autophagy in the Adipose Tissue 171
Role of Ghrelin in the Regulation of Apoptosis and Autophagy in Adipose Tissue 172
The Ghrelin System 172
Ghrelin as a Survival Factor in Adipose Tissue 173
Ghrelin and Autophagy 174
Discussion 174
Acknowledgments 175
References 175
II. Autophagy and Intracellular Pathogens 178
7 Intracellular Pathogen Invasion of the Host Cells: Role of a-Hemolysin-Induced Autophagy 180
Introduction 181
Staphylococcus Aureus 181
Staphylococcus aureus, a Pathogen with a Dual Lifestyle 181
Interaction of S. aureus with the Autophagic Pathway 182
The S. Aureus a-hemolysin, a Key Secreted Virulence Factor 185
Pore-Forming Toxin a-Hemolysin 185
ADAM 10, the Hla Receptor in Host Cells 186
Hla is Capable of Inducing an Autophagic Response 186
Discussion 187
References 188
8 Modulation of Autophagy by Herpesvirus Proteins 190
Introduction 191
Inhibition of Autophagy by Herpesvirus Proteins 192
Modulation of the Autophagy Signaling Pathways 193
Inhibition of the Beclin-1 Initiation Complex 195
Inhibition of the LC3 Conjugation Complex 197
Inhibition of the Maturation Complex 197
Autophagy Activation by Herpesviruses 198
Herpesviridae Proteins that Activate Autophagy 199
Activation of Autophagy by Viral Nucleic Acids 200
Conclusion 201
Acknowledgments 201
References 201
9 Autophagy Induced by Varicella-Zoster Virus and the Maintenance of Cellular Homeostasis 204
Introduction 205
Varicella-Zoster Virus 205
The Disease Varicella 206
Characteristic Exanthems of Varicella and Herpes Zoster 206
Varicella Exanthem 206
Herpes Zoster Dermatomal Exanthem 207
Autophagy and its Visualization by Confocal Microscopy 207
Autophagosomes in the Exanthems of Varicella and Herpes Zoster 208
Evidence for ER Stress and Unfolded Protein Response 210
Acknowledgments 211
References 211
10 Autophagy and Hepatitis B Virus 214
Introduction 215
The HBV Life Cycle 215
Mechanism of HBV-Induced Autophagy 217
Autophagy on HBV Replication 218
Autophagy and HBV-Induced Hepatocarcinogenesis 219
Conclusion 220
References 220
III. Autophagy and Immunity 222
11 Toll-Like Receptors Serve as Activators for Autophagy in Macrophages Helping to Facilitate Innate Immunity 224
Introduction 225
Toll-Like Receptors 226
Autophagy 227
Initial Reports that Linked Autophagy to the Clearance of Intracellular Pathogens 228
TLR-Induced Autophagy 229
Discussion 232
Acknowledgments 233
References 233
12 Autophagy in Antigen Processing for MHC Presentation to T Cells 236
Introduction 237
Cytosolic Antigen Presentation on MHC Class II Molecules 238
Autophagy Regulation of Phagocytosis 240
Antigen Packaging for Cross-Presentation Via Macroautophagy 241
Regulation of MHC Class I Antigen Processing by Macroautophagy 241
Autophagy and Autoimmunity 242
Discussion 242
Acknowledgments 243
References 243
13 Autophagy Controls the Production and Secretion of IL-1ß: Underlying Mechanisms 246
Introduction 247
Interleukin-1ß: Biological Functions and Regulation 247
Role of Autophagy in Interleukin-1ß Secretion 248
Autophagy Controls Inflammasome Activation 249
IL-1ß and Inflammasome Components are Degraded in Autophagosomes 249
Autophagy and Innate Th17 Immune Responses 250
Autophagy and Inflammatory Diseases 251
Conclusion 252
References 253
14 Role of Autophagy in P2X7 Receptor-Mediated Maturation and Unconventional Secretion of IL-1ß in Microglia 256
Introduction 257
Role of Lysosomes in the Maturation of IL-1ß 258
Conventional and Secretory Lysosomes 258
Involvement of Lysosomal Enzymes in the Processing of Pro-IL-1ß 258
Autophagy Might Regulate the Maturation and Secretion of IL-1ß 260
Role of Autophagy in the Innate Immune System 260
Control of the Maturation and Secretion of IL-1ß by Autophagy 260
P2X7R-Mediated Maturation and Unconventional Secretion of IL-1ß 262
Functional Expression of P2X7R in Microglia 262
P2X7R-Mediated Unconventional Secretion Pathway for mIL-1ß 263
P2X7R-Mediated Regulation of Autophagy 264
Role of Autophagy in the P2X7R-Mediated Maturation and Secretion of IL-1ß 265
P2X7R-Mediated Secretion of IL-1ß as a Therapeutic Target in Neurodegenerative Disease 265
Acknowledgments 266
References 266
15 Autophagy Restricts Interleukin-1ß Signaling via Regulation of P62 Stability 268
Introduction 269
Role of Atg16L1 in TLR Signaling 270
Regulation of p62 Stability and IL-1ß Signal Transduction by Autophagy 270
Regulation of P62 Ubiquitination by Atg16L1 271
Discussion 271
Acknowledgments 273
References 273
16 Roles of Autophagy in the Thymic Epithelium 276
Introduction 277
Thymic Epithelium 277
Autophagy 278
Evidence for Autophagy in the Thymic Epithelium 279
Evaluation of Epithelial Autophagy in T Cell Selection 281
Implication of Autophagy in Delivering Antigens to the MHC Class II Compartment 281
Thymus Grafts from Autophagy-Deficient Embryos 281
Investigation of Autophagy in Medullary Epithelial Cells 282
Deletion of Autophagy-Related Genes in Thymic Epithelial Cells 283
Conclusion 284
References 284
IV. Autophagy: General Applications 286
17 The Role of Autophagy Receptors in Mitophagy 288
Introduction 289
Mitochondrial Dynamics 289
General Autophagy 290
Selective Autophagy 291
Autophagy Receptors 292
p62 and NBR1 292
NDP52 and Optineurin 295
Mitophagy 295
Removal of Damaged Mitochondria 296
Mitophagy Receptors: Atg32, BNIP3 and BNIP3L/NIX 297
Discussion 299
Acknowledgments 299
References 299
18 The Role of Parkin and PINK1 in Mitochondrial Quality Control 302
Introduction 303
Parkinson’s Disease and Mitochondrial Dysfunction 304
Parkin and PINK1 Mutant Flies 305
Stabilization of PINK1 on Mitochondria 306
PINK1 Activity on the Mitochondria 309
Parkin: A PD-Associated E3-Ubiquitin Ligase 309
PINK1-Mediated Recruitment of Parkin onto Mitochondria 311
Parkin-Mediated Ubiquitination of Mitochondrial Proteins 311
Parkin/PINK1-Mediated Mitophagy 313
Mitophagy and Neurons 313
Discussion 314
References 315
19 Autophagy Degrades Endocytosed Gap Junctions 318
Introduction 319
Gap Junction Structure and Function 319
Results 320
Gap Junction Endocytosis Generates Cytoplasmic Double-Membrane Vesicles 320
Endocytosed Gap Junctions are Degraded by Autophagy 322
Structural Elements Warrant the Autophagic Degradation of Endocytosed Gap Junctions 323
Potential Other Degradation Pathways for Endocytosed Gap Junctions 324
Signals that Prime Gap Junctions for Endocytosis and Direct them to Autophagic Degradation 325
Discussion 326
Conclusion 327
Acknowledgments 327
References 328
Index 332
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 β 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-1β (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...
| Erscheint lt. Verlag | 16.2.2015 |
|---|---|
| Sprache | englisch |
| Themenwelt | Sachbuch/Ratgeber ► Gesundheit / Leben / Psychologie |
| Medizin / Pharmazie ► Medizinische Fachgebiete ► Dermatologie | |
| Studium ► 1. Studienabschnitt (Vorklinik) ► Histologie / Embryologie | |
| Studium ► 2. Studienabschnitt (Klinik) ► Pathologie | |
| Studium ► Querschnittsbereiche ► Infektiologie / Immunologie | |
| Naturwissenschaften ► Biologie ► Zellbiologie | |
| Technik | |
| ISBN-10 | 0-12-801053-3 / 0128010533 |
| ISBN-13 | 978-0-12-801053-2 / 9780128010532 |
| Haben Sie eine Frage zum Produkt? |
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