Autophagy in Infection and Immunity (eBook)

Preface 6
Contents 8
Contributors 10
An Overview of the Molecular Mechanism of Autophagy 15
1 Introduction 16
2 Molecular Mechanism of Autophagy 19
2.1 Induction and Regulation of Autophagy 19
2.2 The Cvt Pathway and Other Selective Types of Autophagy 24
2.3 Phosphatidylinositol 3-Kinase Complex 27
2.4 Two Ubiquitin-Like Protein Conjugation Systems 29
2.5 Atg9 and Its Cycling Systems 33
2.6 De Novo Vesicle Formation 35
2.7 Vesicle Docking and Fusion with the Vacuole 37
2.8 Vesicle Breakdown and Recycling of the Resulting Macromolecules 38
3 Conclusion 39
References 39
Macroautophagy Signaling and Regulation 47
1 Introduction 48
2 Signaling Pathways 51
2.1 TOR-Dependent Signaling Pathways 51
2.1.1 mTORC1 52
2.1.2 mTORC2 54
2.1.3 Ampk 54
2.1.4 Downstream Targets of mTOR 55
2.2 mTOR-Independent Pathways 55
2.3 Other Pathways 56
2.3.1 eIF2.a. Kinases 56
2.3.1.1 PERK 56
2.3.1.2 PKR 57
2.3.1.3 GCN2 57
2.3.2 MAP Kinases 57
2.3.2.1 p38.MAPK 57
2.3.2.2 Extracellular Signal-Regulated Kinases 58
2.3.2.3 c-Jun N-Terminal Kinases 58
2.3.3 Protein Kinases C 58
2.3.4 DAP Kinases 59
2.3.5 Heterotrimeric G Proteins 59
2.3.6 NF-.k.B 59
2.3.7 Sphingolipids 60
3 Autophagosome Formation 60
3.1 Atg1 and Its Partners 60
3.2 Atg6/Beclin 1 61
3.2.1 Negative Regulators 62
3.2.2 Positive Regulators 64
3.3 Post-translational Modifications of Atg Proteins 64
3.3.1 Ubiquitin-Like Conjugated Systems 65
3.3.2 Atg4 and ROS 65
3.3.3 Atg Acetylation 65
3.4 Transcriptional Regulation of Atg Proteins 66
3.5 The Cytoskeleton 66
4 Maturation Step 67
4.1 Morphology and Definition of Late Stages of Autophagy 67
4.2 Regulation of the Maturation Events 67
4.2.1 SNAREs 68
4.2.2 Rab Proteins 68
4.2.3 ATPases 68
4.2.3.1 v-ATPases 68
4.2.3.2 AAA ATPases 69
4.2.4 ESCRT and Hrs 69
4.2.5 Endo/lysosomal Proteins 70
4.2.5.1 LAMP-2 70
4.2.5.2 DRAM 70
4.2.5.3 Recycling Molecules 70
4.2.6 Microtubules 71
4.3 Signaling and Maturation of Autophagosomes 71
4.3.1 MAPKs 71
5 How Autophagy Can Be Manipulated 72
6 Conclusions 73
References 74
Physiological Functions of Autophagy 85
1 Introduction 85
2 Physiological Functions of Autophagy 87
2.1 Maintenance of the Amino Acid Pool 87
2.2 Intracellular Quality Control 88
2.3 Selective Degradation by Autophagy 89
2.4 Development and Cell Death 90
2.5 Tumor Suppression 91
2.6 Anti-Aging 92
3 Conclusion 93
References 93
Autophagy and Lymphocyte Homeostasis 99
1 Introduction 100
2 Regulation of T Cell Homeostasis by Cytokines and MHC/Peptide Ligands 100
2.1 Cytokines in T Cell Homeostasis 101
2.2 TCR–MHC Interactions in T Cell Homeostasis 101
3 Regulation of T Cell Homeostasis by the Intrinsic and Extrinsic Apoptotic Pathways 102
3.1 Extrinsic Pathway Apoptosis in T Cell Homeostasis 102
3.2 Intrinsic Apoptosis Pathway in T Cell Homeostasis 103
4 Autophagy Induction in T Lymphocytes 104
5 Autophagy: Dual Roles in T Cell Survival and Death 106
5.1 Autophagy Contributes to Homeostatic T Cell Survival In Vivo 106
5.2 Autophagy Contributes to T Cell Death 108
5.3 Autophagy as a Paradoxical Mediator of Both Survival and Death in T Cells? 109
6 Autophagy in T Cell Proliferation 109
6.1 Autophagosome Formation in T Cell Proliferation 110
6.2 A Role for Autophagy Genes in T Cell Proliferation Outside of Autophagosome Formation? 111
7 Autophagy in B Lymphocytes 111
8 Conclusion 112
References 113
Autophagy and Innate Recognition Systems 120
1 Introduction 121
2 Autophagy and Viral Sensing: Patrolling the Fort 122
2.1 Innate Viral Recognition 122
2.2 Autophagy in Innate Viral Recognition Through TLRs 123
2.3 The Role of Atg5/Autophagy in TLR9 Signaling in pDCs 124
2.4 Negative Regulation of RLRs via the Atg5–Atg12 Conjugate 125
3 Interplay Among Innate Recognition, Induction of Autophagy and Phagocytosis: Securing the Fort 126
3.1 Phagocytosis 126
3.2 Convergence of Autophagy and Phagocytosis 126
3.2.1 TLR Signals Induce Autophagy to Clear Intracellular Pathogens 127
3.2.2 TLR-Induced Phagocytosis Utilize Machinery of Autophagy to Clear Extracellular Pathogens 128
4 Cytokine Feedback: Beating the Battle Drum 130
5 Concluding Remarks 130
References 131
Autophagy in MHC Class II Presentation of Endogenous Antigens 135
1 Introduction 136
2 Source Proteins of Peptide Ligands For MHC Class II Molecules 137
3 Intracellular Antigen Processing onto MHC Class II Proteins 139
4 Macroautophagy as a Source of MHC Class II Ligands 141
4.1 Model Antigens 142
4.2 Tumor Antigens 142
4.3 Intracellular Pathogens as a Source of Macroautophagy-Dependent MHC Class II Antigens 143
4.3.1 .Mycobacterium tuberculosis 143
4.3.2 Epstein–Barr Virus (EBV) 144
4.4 Self-Antigens as a Source of MHC Class II Epitopes After Macroautophagy 144
4.5 Macroautophagy in Professional Antigen-Presenting Cells 145
4.5.1 Tolerance Induction by DCs 145
4.5.2 Immunological Synapse 145
4.6 Macroautophagy in Epithelial Cells 146
4.6.1 Possible Roles of Autophagy in Central Tolerance 146
4.6.2 Peripheral Tolerance 147
4.6.2.1 Extrathymic Expression of Aire 147
4.6.2.2 Association Between Macroautophagy Regulation and Crohn’s Disease 147
4.6.2.3 Autophagy and the Allogeneic Response 147
5 Conclusions 148
References 149
Role of Autophagy and Autophagy Genes in Inflammatory Bowel Disease 153
1 Introduction 154
2 Inflammatory Bowel Disease 155
2.1 Clinical Aspects of Inflammatory Bowel Disease in Humans 155
2.2 Murine Models of Colitis 156
2.3 Murine Models for Disease of the Small Intestine 157
2.4 The Role of Bacteria in Inflammatory Bowel Disease 158
3 Autophagy and Crohn’s Disease 160
3.1 Identification of .ATG16L1. and .IRGM1. as Crohn’s Disease Susceptibility Genes 160
3.2 The Role of Atg16L1 in Autophagy 161
3.3 The Role of IRGM1 in Autophagy 163
4 The Role of Autophagy in Intestinal Biology 164
4.1 Two Mouse Models to Examine Atg16L1 Function In Vivo 164
4.2 Loss of Atg16L1 Leads to an Increased Inflammatory Response and Increased Expression of the Proinflammatory Cytokine IL-1. 165
4.3 Mice with Reduced Atg16L1 Expression Reproduce Aspects of Crohn’s Disease Pathology, and Reveal a Cellular Target for the 167
5 Conclusion and Future Perspectives 171
References 173
Autophagy in Immunity Against .Mycobacterium tuberculosis.: a Model System to Dissect Immunological Roles of Autophagy 180
1 Introduction: Autophagy as an Antimicrobial Defense Mechanism Against Bacteria, Protozoan Parasites and Viruses 181
2 .M. tuberculosis. Parasitizes Host Macrophages 183
3 Autophagy Eliminates Intracellular .M. tuberculosis 184
4 Unique Properties of Autolysosomes in Microbial Killing 184
5 Autophagy is an Effector of Th1/Th2 Polarization 185
6 Immunity-Related GTPases (IRGs) Regulate Autophagy in Antimicrobial Defense and Inflammation 187
7 Autophagy is an Effector of Pattern Recognition Receptor Signaling 189
8 Conclusions and a Model 193
References 194
Autophagy in Immunity Against Intracellular Bacteria 200
1 Autophagy as an Immune Defense Mechanism Against Bacteria 202
2 Autophagy of .Salmonella enterica. Serovar Typhimurium 202
2.1 Salmonella. in Disease 202
2.2 Lifestyle of Intracellular .S .typhimurium. in Mammalian Cells 203
2.3 Virulence of .S .typhimurium.: T3SS and Effectors 205
2.4 Autophagy in Defense Against .S .typhimurium 206
2.5 Multiple Fates of Intracellular .S .typhimurium 207
3 Autophagy of .Listeria monocytogenes 207
3.1 L. monocytogenes. in Disease 207
3.2 Lifestyle of .L. monocytogenes. in Mammalian Cells 208
3.3 Virulence Factors of .L. monocytogenes 208
3.4 Autophagy .of L. monocytogenes 210
3.5 Spacious .Listeria.-Containing Phagosomes 212
3.6 Multiple Fates of Different .L. monocytogenes. Populations 214
4 Autophagy of .Shigella flexneri. and Other Intracellular Bacteria 214
5 Bacterial Autophagy in Inflammatory Bowel Disease 216
6 Summary 219
References 220
Group A Streptococcus: A Loser in the Battle with Autophagy 227
1 Invasion of Host Cells by Group A Streptococcus 228
2 Escape of GAS from Endosomes 228
3 Capture of GAS by Autophagy 229
4 Winner or Loser? 230
5 Differences from Canonical Autophagy 232
6 Autophagy in Staphylococcus aureus Infection 234
7 Concluding Remarks 235
References 235
Autophagy Subversion by Bacteria 237
1 Coxiella burnetii 238
1.1 Bacterial Morphology and Antigenic Variation 238
1.2 Coxiella burnetii. Type IV Secretion System 239
1.3 The C. burnetii Replicative Niche 240
1.4 The Autophagic Pathway Favors C. burnetii Infection 240
2 Legionella pneumophila 242
2.1 L. pneumophila .Generates a Customized Bacterial Compartment 242
2.2 The Type IV Secretion System Encoded by the .dot./.icm. Gene Complex 243
2.3 L. pneumophila. Exploits the Host Autophagic Pathway 243
3 Staphylococcus aureus 245
3.1 .S. aureus. Small Cell Variants 245
3.2 The Global Regulator Systems .agr. and .sar 245
3.3 Intracellular Survival of .S. aureus.: Escaping from the Phagosomal Compartment 246
3.4 .S. aureus. Subverts the Autophagy Pathway 247
4 Porphyromonas gingivalis 248
4.1 The Intracellular Life of .P. gingivalis. and the Autophagy Pathway 249
4.2 The Role of Gingipains 250
5 Anaplasma phagocytophilum 251
5.1 A. phagocytophilum. Interacts with the Autophagic Pathway 251
5.2 The Autophagic Pathway Favors A. phagocytophilum Infection 252
6 Brucella abortus 252
6.1 The Intracellular Niche of .B. abortus 252
7 Concluding Remarks 255
Autophagy in Immunity Against Toxoplasma gondii 261
1 Introduction 262
2 CD40 and T. gondii Infection 263
2.1 CD40 Induces Toxoplasmacidal Activity by Vacuole-Lysosomal Fusion 264
2.2 CD40 Induces Toxoplasmacidal Activity Through Autophagy 266
3 Relevance of Autophagy in T. gondii .Infection 269
4 Conclusion 270
References 271
Autophagy in Mammalian Antiviral Immunity 276
1 Introduction 277
2 Autophagy in Combat with Viruses 277
2.1 Autophagy Protects Against Neurotropic Viral Infections 279
2.1.1 Sindbis Virus 279
2.2 HSV-1 280
2.3 Potential Protective Mechanisms of Autophagy in Mammalian Viral Diseases 282
3 Viruses Conduct Evasive Maneuvers 287
3.1 HSV-1 Mounts a Concerted Attack on Autophagy 287
3.2 Viral Bcl-2 Homologs Antagonize Host Autophagy 289
3.3 Autophagy Evasion as a Common Virulence Mechanism? 290
4 Conclusion 291
References 291
Something Old, Something New: Plant Innate Immunity and Autophagy 295
1 Introduction 296
2 Autophagy in Plant Development and Senescence 296
3 Autophagy and Plant Innate Immunity 297
4 Does Autophagy Limit Death Signals? A Model to Explain Regulation of HR-PCD 300
5 Autophagy During the Basal Immune Response 303
6 Plant RNA Viruses and the Chloroplast 303
6.1 Physiological Consequences of Viruses in the Chloroplast 304
6.2 Virus-Induced Transport of Chloroplast into the Vacuole: Chlorophagy or Executed Innocent Bystander? 305
7 Plant Viral Clearance in the Vacuole 308
8 Conclusions 310
References 310
Autophagy in HIV-Induced T Cell Death 315
1 Introduction 316
2 HIV Replication Cycle 317
3 Highly Active Antiretroviral Therapy and Autophagy-Inducing Drugs 318
4 Mechanisms Leading to Immunodeficiency 320
5 Role of Autophagy in Env-Mediated CD4 T Cell Death 321
6 Role of Autophagy in HIV-Infected Cells 323
7 Conclusion 323
References 324
Subversion of the Cellular Autophagy Pathway by Viruses 330
1 Introduction 330
2 Viruses for Which the Autophagy Pathway is Advantageous 332
3 What Can Autophagy Do for a Virus? 334
4 Conclusion 338
References 339
Index 341