Protein degradation. V.3, cell biology of the ubiquitin-proteasome system /

Contents 7
Preface 13
List of Contributors 15
1 Ubiquitin: A New Player in the Peroxisome Field 17
1.1 Introduction 17
1.2 Matrix Protein Import into Peroxisomes is Mediated by Cycling Receptors 18
1.3 Pex5p is Monoubiquitinated in Wild-type Cells, but Polyubiquitinated in Late-acting pex Mutants 20
1.4 Ubiquitination of Pex18p 25
1.5 Role for the RING Finger and AAA Peroxins in Pex5p Ubiquitination and Recycling 25
1.6 Pex5p Monoubiquitination: A Role in Receptor Recycling 28
1.7 Conclusions/Future Prospects 30
Acknowledgements 31
References 32
2 The Ubiquitin Proteasome System and Muscle Development 37
2.1 Introduction 37
2.2 Muscle Histology 37
2.3 UPS and Developing Muscle 39
2.3.1 Ubiquitin-dependent Degradation of MyoD 39
2.3.2 Degradation of MyoD by SCF(MAFbx) 40
2.3.3 Other Muscle Regulatory Factors 42
2.4 UPS and Organizing Muscle 44
2.4.1 Ozz-E3-dependent 尾-Catenin Regulation in the Muscle 44
2.4.2 Regulation of Myosin Assembly by CHN-1 and UFD-2 45
2.5 UPS and Muscle Destruction or Degeneration 47
2.5.1 N-end Rule and Muscle Atrophy 47
2.5.2 MuRFs, E3 Enzymes in Atrophying Muscles 49
2.5.3 Atrogin-1/MAFbx Function in Muscle Atrophy 50
2.5.4 Activation of Muscle-atrophy Pathways 52
2.6 Concluding Remarks 53
References 55
3 The COP9 Signalosome: Structural and Biochemical Conservation and Its Roles in the Regulation of Plant Development 64
3.1 Introduction 64
3.2 The Plant COP9 Signalosome 65
3.3 CSN Involvement in the Ubiquitin\u2013Proteasome Pathway 68
3.4 Plant CSN Biochemical Activities 71
3.4.1 Deneddylation 73
3.4.2 Subcellular Partitioning 76
3.5 CSN Functions in Plant Development 76
3.5.1 Floral Development 78
3.5.2 Responses to Plant Hormones 79
3.5.3 Disease Resistance 81
3.5.4 Photomorphogenesis 82
3.6 Conclusions 83
References 84
4 Ubiquitin and Protein Sorting to the Lysosome 92
4.1 Introduction 92
4.2 Identification of Ubiquitin as an Endosomal Sorting Signal 94
4.3 Ubiquitin-mediated Sorting at the Endosome: The MVB Sorting Machinery 95
4.3.1 Endosome-associated Ubiquitin Interacting Domains: Structure and Function 95
4.3.2 The Hrs\u2013STAM Complex and the Endosomal Clathrin Coat 97
4.3.3 GGA and Tom1: Alternative Sorting Adapters? 98
4.3.4 The ESCRT Machinery 100
4.3.5 Vps4\u2013SKD1 102
4.4 Ubiquitin Ligases and Endosomal Sorting 103
4.4.1 Nedd4 Family 103
4.4.2 c-Cbl 104
4.5 Endosomal DUBs 105
4.5.1 Ubp1 and Ubp2 105
4.5.2 Doa4 105
4.5.3 UBPY 106
4.5.4 AMSH 108
4.6 Polyubiquitin Linkages and Endocytosis 109
4.6.1 Proteasome Involvement in Endocytic Sorting 109
4.6.2 K63-linked Ubiquitin 110
4.7 Future Directions 110
Acknowledgements 110
References 110
5 ISG15-dependent Regulation 119
5.1 Introduction and Overview 119
5.2 The Discovery of ISG15 120
5.3 Structure and Properties of the ISG15 Protein 121
5.4 The ISG15 Conjugation Pathway 125
5.4.1 Activation of ISG15 by UbE1L 126
5.4.2 UbcH8 is an ISG15-specific Conjugating Enzyme 128
5.4.3 Candidate ISG15-specific Ligases 132
5.5 Regulation of Intracellular ISG15 Pools 136
5.6 Functional Roles for ISG15 138
5.6.1 ISG15 as an Extracellular Cytokine 138
5.6.2 Role of ISG15 in the Antiviral Response 140
5.6.3 ISG15 and Early Events of Pregnancy 141
5.7 Perspective 142
Acknowledgements 142
References 142
6 The Role of the Ubiquitin\u2013Proteasome Pathway in the Regulation of the Cellular Hypoxia Response 148
6.1 Overview of the Hypoxia Response 148
6.2 Players in the Hypoxia-response Signalling Pathway 149
6.2.1 Hypoxia-inducible Factors 149
6.2.2 Prolyl-hydroxylase Domain-containing Enzymes and FIH 151
6.3 pVHL-dependent Degradation of HIF-1伪 152
6.4 Siah-dependent Regulation of PHD 155
6.5 Other Examples of Altered Ubiquitination During Hypoxia 156
6.5.1 p53/Mdm2 156
6.5.2 MyoD 158
6.5.3 CREB 158
6.5.4 SUMOylation 158
6.6 Ischemia Model 159
6.7 Regulation of the Ubiquitin System in Hypoxia 159
6.8 Concluding Remarks 160
References 160
7 p97 and Ubiquitin: A Complex Story 165
Abstract 165
7.1 Introduction 165
7.2 Interactions of Ubiquitin, p97 and Adaptors 169
7.2.1 Ubiquitin-binding Domains and Motifs 169
7.2.2 p97 Interacts Directly With Ubiquitin 176
7.2.3 p97 Adaptor Proteins Can Also Interact With Ubiquitin 177
7.2.4 p97-p47 Structure as a General Model for UBX Domain Binding: A Level of Similarity Between UBX Domains 179
7.2.5 The Interaction of p97 With Ubiquitin Ligases 181
7.2.6 The Interactions of p97 With Deubiquitinating Enzymes 182
7.3 The Cellular Roles of p97 and Ubiquitin 182
7.3.1 ERAD 183
7.3.1.1 The ERAD Pathway 183
7.3.1.2 Recognition of ERAD Substrates 185
7.3.1.3 Translocation into the Cytosol 186
7.3.1.4 Mono/diubiquitin Conjugation 186
7.3.1.5 Polyubiquitination by E4 Factors 187
7.3.1.6 Release from the ER Membrane 187
7.3.1.7 Transport to the Proteasome 188
7.3.1.8 The Proteasome in ERAD 191
7.3.2 Other Ubiquitin-dependent Processes That Involve p97 191
7.3.2.1 p97 and the Degradation of Cytoplasmic Substrates 191
7.3.2.2 p97 and the Proteasome in Transcription-factor Processing 191
7.3.2.3 p97 and Other Ubiquitin-binding Adaptors 192
7.3.2.4 p97 and Ubiquitin in Membrane Fusion 193
7.4 The Action of p97 194
7.4.1 p97 as a Chaperone 195
7.4.2 p97 and NSF: SNARE Disassembly Machines 195
7.4.3 p97 Liberates Polyubiquitinated Substrates from the ER Membrane 196
7.4.4 p97 as a Segregase 196
7.5 When Things Go Wrong: p97 in Disease 197
7.6 Conclusions 198
Acknowledgments 200
References 200
8 Cdc48 (p97) and Its Cofactors 210
8.1 Introduction 210
8.2 Cdc48 Cofactors 211
8.2.1 Cofactor Families 213
8.2.1.1 UBX Domain Proteins 213
8.2.1.2 Ufd1/Npl4 213
8.2.1.3 Other Cofactors 214
8.2.2 Cofactor Functions 215
8.2.2.1 Substrate-recruiting Cofactors 215
8.2.2.2 Substrate-processing Cofactors 215
8.2.2.3 Additional Functions of Cofactors 217
8.3 Cellular Functions 217
8.3.1 Cdc48(Ufd1/Npl4) 218
8.3.1.1 Protein-degradation Pathways 218
8.3.1.2 Cell Cycle Regulation 219
8.3.2 Cdc48(Shp1) 220
8.3.2.1 Membrane Fusion 220
8.3.2.2 Protein Degradation 221
8.3.3 Further Functions 222
8.4 Outlook 222
Acknowledgements 223
References 223
9 Deubiquitinating Enzymes, Cell Proliferation, and Cancer 228
9.1 Introduction 228
9.1.1 Ubiquitination 228
9.1.2 Deubiquitination 229
9.2 DUBs, Oncogenes, and Cell Transformation 230
9.2.1 USP6/Tre-2/Tre-17 230
9.2.2 Unp/Usp4/Usp15 231
9.2.3 DUBs and NF魏B Signalling 233
9.2.4 USP7/HAUSP and p53 234
9.2.5 USP33/VDU1, USP20/VDU2, and von Hippel\u2013Lindau Disease 236
9.2.6 USP1, Fanconi Anaemia, and DNA Repair 236
9.2.7 DUBs Associated with BRCA1 and BRCA2 237
9.2.8 The Cytokine-inducible DUB-1/DUB-2/USP17 Family and Regulation of Cell Growth 239
9.3 Conclusions and Perspectives 239
References 241
Index 248