Cellular Biology of the Endoplasmic Reticulum (Progress in Molecular and Subcellular Biology, 59)

This series gives an insight into the most current, cutting edge topics in molecular biology, including applications in biotechnology and molecular medicine. In the recent years, the progress of research in the frontier area of molecular and cell biology has resulted in an overwhelming amount of data on the structural components and molecular machineries of the cell and its organelles and the complexity of intra-and intercellular communication. The molecular basis of hereditary and acquired diseases is beginning to be unravelled, and profound new insights into development and evolutionary biology, as well as the genetically driven formation of 3D biological architectures, have been gained from molecular approaches. Topical volumes, written and edited by acknowledged experts in the field, present the most recent findings and their implications for future research. Preface Contents Chapter 1: A View of the Endoplasmic Reticulum Through the Calreticulin Lens 1.1 Introduction 1.2 The ER and ER Ca2+ 1.3 Calreticulin, a Key Ca2+-Binding ER-Resident Protein Required for Optimal ER Function 1.4 Calreticulin, Looking Outside from the ER and the Cell 1.5 Calreticulin, the View to the Future References Chapter 2: Structural Analysis of Calreticulin, an Endoplasmic Reticulum-Resident Molecular Chaperone 2.1 Introduction 2.2 Primary Structures of Calr and Related Proteins 2.3 Higher Order Structures of Calr and Related Proteins 2.4 Calr Structure-Function Relationships 2.5 Summary Points 2.6 Future Issues References Chapter 3: The Role of Endoplasmic Reticulum Chaperones in Protein Folding and Quality Control 3.1 Introduction 3.2 BiP Binding Cycle 3.2.1 BiP Organization and Structure 3.2.2 BiP Binding Specificity 3.2.3 Substrate Delivery to BiP 3.2.4 Substrate Release from BiP 3.2.5 BiP Modification 3.3 Calnexin and Calreticulin Binding Cycle 3.3.1 Calnexin/Calreticulin Organization and Structure 3.3.2 Calnexin/Calreticulin Binding Specificity 3.3.3 Delivery to the Calnexin/Calreticulin Cycle 3.3.4 Calnexin/Calreticulin Substrate Release and Rebinding 3.3.5 Terminal Release of Substrates from Calnexin/Calreticulin Binding Cycle 3.3.6 Calnexin/Calreticulin-Associated Factors 3.3.7 Calnexin/Calreticulin Modification 3.4 Concluding Remarks 3.5 Summary Points 3.6 Future Issues References Chapter 4: Proteins Interacting with STIM1 and Store-Operated Ca2+ Entry 4.1 Introduction 4.1.1 ER Proteins 4.1.1.1 Positive Regulators of SOCE: ITPRs, STIMATE, UNC93B1, PMP22, ANO8, Prx-4 and POST ITPRs STIMATE UNC93B1 PMP22 ANO8 Prx-4 POST 4.1.1.2 Negative Regulators of SOCE: SARAF, SURF4, STING, TMEM178 and PDIA3 SARAF SURF4 STING TMEM178 PDIA3 Sigma Receptors 4.1.2 Plasma Membrane Proteins 4.1.2.1 Alternate STIM1 Targets: Voltage- and Ligand-Gated Ca2+ Channels: VGCCs, AMPAR and NMDAR VGCCs AMPAR NMDAR 4.1.2.2 Plasma Membrane Protein CLCA2 CLCA2 4.1.3 Cytoplasmic Proteins 4.1.3.1 Signaling Proteins Golli-MBP Calmodulin CRACR2 EFHB -SNAP BAG3 4.1.3.2 Cytoskeleton Proteins: Controlling STIM1 Trafficking EB1 APC 4.2 Conclusions 4.3 Summary Points 4.4 Future Issues References Chapter 5: Endoplasmic Reticulum (ER) and ER-Phagy 5.1 The Endoplasmic Reticulum (ER) 5.2 ER-Phagy 5.2.1 The ER Inside the Lysosomes: Historical Evidences 5.2.2 The Discovery of ER-Phagy Receptors 5.2.3 ER-Phagy in Yeast 5.2.4 The Many Ways to Deliver the Mammalian ER to the Endolysosomal Compartments for Clearance 5.2.4.1 Starvation-Induced Macro-ER-Phagy 5.2.4.2 ER Stress-Induced Macro-ER-Phagy 5.2.4.3 Micro-ER-Phagy to Recover from ER Stress 5.2.4.4 Other LC3-Binding Proteins Involved in ER Turnover 5.2.4.5 ER-to-Lysosome-Associated Degradation (ERLAD) 5.2.5 ER-Phagy in Health and Disease 5.3 Summary Points 5.4 Future Issues References Chapter 6: Defects in Protein Folding and/or Quality Control Cause Protein Aggregation in the Endoplasmic Reticulum 6.1 Many Proteins Can Aggregate in the ER 6.2 Protein Aggregation and Amyloid Fibril Formation Initiate Through a Nucleation Event 6.3 Intrinsic and Extrinsic Factors Affect Protein Aggregation and Amyloid Fibril Formation 6.3.1 Increased ß-Sheet Propensity Contributes to Protein Aggregation 6.3.2 Protein Aggregation Is Dependent on Protein Concentration 6.3.3 Oxidative Stress Causes Protein Aggregation 6.3.4 ATP Is Required to Prevent Protein Aggregation 6.4 ER Quality Control Ensures Only Properly Folded Proteins Traffic to the Golgi Compartment 6.4.1 The Calnexin/Calreticulin (CANX/CALR) Cycle Prevents Aggregation of Misfolded Glycoproteins 6.4.2 BiP/GRP78 Maintains Proteins in a Folding-Competent Conformation, Prevents Aggregation and Promotes Disaggregation 6.5 The Unfolded Protein Response (UPR) Is an Adaptive Response to Prevent Misfolded Protein Accumulation in the ER 6.6 Protein Aggregation in the ER Contributes to Human Disease 6.6.1 1-Antitrypsin (1-AT) Aggregation Causes Liver Disease 6.6.2 FVIII Aggregation Causes Hemophilia A 6.6.3 Proinsulin High Molecular Weight (HMW) Aggregation Is an Early Step in β-Cell Failure in Type 2 Diabetes (T2D) 6.6.4 Cystic Fibrosis Is Due to Mutations that Cause Misfolding of CFTR 6.7 Therapeutic Strategies May Prevent ER Protein Aggregation-Associated Diseases 6.7.1 Chemical Chaperones Buffer Protein Folding 6.7.2 Antioxidants Can Improve ER Protein Folding 6.7.3 Preemptive UPR Activation Reduces ER Protein Misfolding 6.8 Conclusions 6.9 Summary Points 6.10 Future Issues References Chapter 7: Roles of Calreticulin in Protein Folding, Immunity, Calcium Signaling and Cell Transformation 7.1 Introduction to the Proteins 7.2 Engagement, Folding and ER Retention of Glycoproteins with Monoglucosylated Glycans 7.3 Glycan-Independent Protein Binding by Calreticulin 7.4 Calreticulin, Cellular Calcium Homeostasis and Calcium Signaling 7.5 Immune Functions of Calreticulin 7.6 Calreticulin C-Domain Mutations in Myeloproliferative Neoplasms 7.7 Summary Points and Future Issues References Chapter 8: Impact of Calreticulin and Its Mutants on Endoplasmic Reticulum Function in Health and Disease 8.1 Introduction 8.2 The Endoplasmic Reticulum 8.2.1 Lipid Synthesis and Transport 8.2.2 Protein Synthesis and Trafficking 8.2.3 ER Stress 8.2.4 Calcium Signaling 8.3 Calreticulin: Role in ER Function in Health and Disease 8.3.1 CALR as a Lectin Chaperone 8.3.2 CALR Mutants and Non-glycan Mediated Protein Interactions 8.3.3 CALR and Ca2+ Signaling 8.3.4 CALR and Lipid Synthesis 8.3.5 CALR Mutants and ER Stress 8.3.6 CALR as a Signaling Molecule 8.4 Summary Points 8.5 Future Issues References Chapter 9: Cancer Biology of the Endoplasmic Reticulum Lectin Chaperones Calreticulin, Calnexin and PDIA3/ERp57 9.1 Introduction 9.2 Expression of CALR in Human Cancers 9.3 Expression of PDIA3 and CANX in Human Cancers 9.4 Cell Surface CALR Signals Immunogenic Cell Death 9.5 Intersection of α-Integrins, CALR and ICD 9.6 Regulation of Oncogenic Signaling by Lectin Chaperones 9.7 Summary Points 9.8 Future Issues References Chapter 10: Maintenance of Endoplasmic Reticulum Protein Homeostasis in Cancer: Friend or Foe 10.1 Introduction 10.2 The Unfolded Protein Response 10.3 ER-Associated Degradation 10.4 Surveillance Mechanisms 10.5 ER Import and Export Systems 10.6 ER Proteostasis Control in Cancer 10.6.1 Oncogenes and Tumour Suppressors 10.6.2 Solid Cancers 10.6.3 Blood Cancers 10.7 Drugging ER Proteostasis in Cancer 10.7.1 IRE1-Targeting Drugs 10.7.2 PERK-Targeting Drugs 10.7.3 Other Drug Targets in ER Proteostasis 10.8 Summary Points 10.9 Future Issues References Chapter 11: IP3 Receptor Biology and Endoplasmic Reticulum Calcium Dynamics in Cancer 11.1 Introduction 11.2 IP3R Structure-Function Relationship 11.3 Cellular and Subcellular Localization of the IP3R 11.4 Intracellular Ca2+ Signaling and Cancer 11.5 The IP3R as Regulator of Autophagy 11.6 The IP3R in Apoptosis 11.7 The Complex Role of the IP3R in Tumorigenesis: An Integrated View 11.7.1 Breast Cancer 11.7.2 Colorectal Cancer 11.7.3 Other Cancers 11.8 IP3Rs Are Targeted by Oncogenes and Tumor Suppressors: A Therapeutic Opportunity? 11.9 Conclusions 11.10 Summary Points 11.11 Future Issues References Chapter 12: Disruption of Endoplasmic Reticulum Proteostasis in Age-Related Nervous System Disorders 12.1 Introduction 12.2 ER Machinery and UPR Signaling 12.3 ER Stress in Neurodegenerative Diseases 12.3.1 IRE1α Pathway 12.3.2 PERK Pathway 12.3.3 ATF6 Pathway 12.3.4 The Folding Machinery and Protein Quality Control 12.4 Diet-Induced Comorbidities: The Road to Deleterious Cascades of ER Stress 12.4.1 Liver 12.4.2 Adipose Tissue 12.4.3 Pancreas 12.4.4 Hypothalamus: Central Nervous System Control of Energy Homeostasis 12.5 Metabolic Syndrome and Neurodegeneration: Cause and Effect Relationship? 12.6 Conclusions 12.7 Summary Points 12.8 Future Issues References Chapter 13: Endoplasmic Reticulum Homeostasis and Stress Responses in Caenorhabditis elegans 13.1 Introduction 13.2 Brief Biology of C. elegans in the Study of ER Homeostasis 13.3 Unfolded Protein Response (UPR) in C. elegans 13.4 UPR and Aging 13.5 Cell-Nonautonomous UPR 13.5.1 Longevity 13.5.2 Chromatin Remodeling 13.6 Interplay Between Redox and the UPR 13.7 UPR and Metabolism 13.7.1 Dietary Restriction (DR) and Food Deprivation 13.7.2 Glycan Metabolism 13.7.3 Phospholids Metabolism 13.7.4 Protein Metabolism 13.8 UPR and RNA World 13.9 UPR and Innate Immunity 13.10 Noncanonical UPR Response in C. elegans 13.10.1 PQN/ABU Genes in Parallel with IRE-1/XBP-1 13.10.2 Autophagy Induction Independent of IRE-1 13.10.3 ER Stress Response in Differentiation 13.10.4 The UPR from outside 13.11 Conclusions 13.12 Summary Points 13.13 Future Issues References Chapter 14: Tardigrada: An Emerging Animal Model to Study the Endoplasmic Reticulum Stress Response to Environmental Extremes 14.1 Introduction: Tardigrada 14.2 Cryptobiosis 14.3 Resistance to Extreme Environmental Conditions 14.4 Protective Mechanisms 14.5 Endoplasmic Reticulum, Stress Response and Tardigrades 14.6 Tardigrades as an Animal Model to Study the ER Stress Response 14.7 Summary Points 14.8 Future Issues References This book provides a comprehensive overview of the biology of the endoplasmic reticulum (ER) and the associated ER proteins, it discusses their structure, function and signaling mechanisms in the cell and their role in disease. This book also offers insights into the practical aspects of research and demonstrates the use of non-mammalian models to study the structure and function of the ER. Written by leading experts in the field, the book enables readers to gain a thorough understanding of current ER biology. It is intended for scientists and clinical researchers working on the endoplasmic reticulum in all its various roles and facets in health and disease. .