Description
Book SynopsisMoonlighting Proteins: Novel Virulence Factors in Bacterial Infections is a complete examination of the ways in which proteins with more than one unique biological action are able to serve as virulence factors in different bacteria.
The book explores the pathogenicity of bacterial moonlighting proteins, demonstrating the plasticity of protein evolution as it relates to protein function and to bacterial communication. Highlighting the latest discoveries in the field, it details the approximately 70 known bacterial proteins with a moonlighting function related to a virulence phenomenon. Chapters describe the ways in which each moonlighting protein can function as such for a variety of bacterial pathogens and how individual bacteria can use more than one moonlighting protein as a virulence factor. The cutting-edge research contained here offers important insights into many topics, from bacterial colonization, virulence, and antibiotic resistance, to protein structure and
Table of Contents
List of Contributors xv
Preface xix
About the Editor xxiii
Part I Overview of Protein Moonlighting 1
1 What is Protein Moonlighting and Why is it Important? 3
Constance J. Jeffery
1.1 What is Protein Moonlighting? 3
1.2 Why is Moonlighting Important? 5
1.2.1 Many More Proteins Might Moonlight 5
1.2.2 Protein Structure/Evolution 5
1.2.3 Roles in Health and Disease 8
1.2.3.1 Humans 8
1.2.3.2 Bacteria 10
1.3 Current questions 11
1.3.1 How Many More Proteins Moonlight? 11
1.3.2 How Can We Identify Additional Proteins That Moonlight and all the Moonlighting Functions of Proteins? 11
1.3.3 In Developing Novel Therapeutics, How Can We Target the Appropriate Function of a Moonlighting Protein and Not Affect Other Functions of the Protein? 12
1.3.4 How do Moonlighting Proteins get Targeted to More Than One Location in the Cell? 12
1.3.5 What Changes in Expression Patterns Have Occurred to Enable the Protein to be Available in a New Time and Place to Perform a New Function? 12
1.4 Conclusions 13
References 13
2 Exploring Structure–Function Relationships in Moonlighting Proteins 21
Sayoni Das, Ishita Khan, Daisuke Kihara, and Christine Orengo
2.1 Introduction 21
2.2 Multiple Facets of Protein Function 22
2.3 The Protein Structure–Function Paradigm 23
2.4 Computational Approaches for Identifying Moonlighting Proteins 25
2.5 Classification of Moonlighting Proteins 26
2.5.1 Proteins with Distinct Sites for Different Functions in the Same Domain 27
2.5.1.1 α‐Enolase, Streptococcus pneumonia 27
2.5.1.2 Albaflavenone monooxygenase, Streptomyces coelicolor A3(2) 29
2.5.1.3 MAPK1/ERK2, Homo sapiens 30
2.5.2 Proteins with Distinct Sites for Different Functions in More Than One Domain 30
2.5.2.1 Malate synthase, Mycobacterium tuberculosis 31
2.5.2.2 BirA, Escherichia coli 31
2.5.2.3 MRDI, Homo sapiens 33
2.5.3 Proteins Using the Same Residues for Different Functions 33
2.5.3.1 GAPDH E. coli 33
2.5.3.2 Leukotriene A4 hydrolase, Homo sapiens 33
2.5.4 Proteins Using Different Residues in the Same/Overlapping Site for Different Functions 34
2.5.4.1 Phosphoglucose isomerase, Oryctolagus cuniculus, Mus musculus, Homo sapiens 34
2.5.4.2 Aldolase, Plasmodium falciparum 36
2.5.5 Proteins with Different Structural Conformations for Different Functions 36
2.5.5.1 RfaH, E. coli 36
2.6 Conclusions 37
References 39
Part II Proteins Moonlighting in Prokarya 45
3 Overview of Protein Moonlighting in Bacterial Virulence 47
Brian Henderson
3.1 Introduction 47
3.2 The Meaning of Bacterial Virulence and Virulence Factors 47
3.3 Affinity as a Measure of the Biological Importance of Proteins 49
3.4 Moonlighting Bacterial Virulence Proteins 50
3.4.1 Bacterial Proteins Moonlighting as Adhesins 52
3.4.2 Bacterial Moonlighting Proteins That Act as Invasins 59
3.4.3 Bacterial Moonlighting Proteins Involved in Nutrient Acquisition 59
3.4.4 Bacterial Moonlighting Proteins Functioning as Evasins 60
3.4.5 Bacterial Moonlighting Proteins with Toxin‐like Actions 63
3.5 Bacterial Moonlighting Proteins Conclusively Shown to be Virulence Factors 64
3.6 Eukaryotic Moonlighting Proteins That Aid in Bacterial Virulence 66
3.7 Conclusions 67
References 68
4 Moonlighting Proteins as Cross‐Reactive Auto‐Antigens 81
Willem van Eden
4.1 Autoimmunity and Conservation 81
4.2 Immunogenicity of Conserved Proteins 82
4.3 HSP Co‐induction, Food, Microbiota, and T-cell Regulation 84
4.3.1 HSP as Targets for T‐Cell Regulation 85
4.4 The Contribution of Moonlighting Virulence Factors to Immunological Tolerance 87
References 88
Part III Proteins Moonlighting in Bacterial Virulence 93
Part 3.1 Chaperonins: A Family of Proteins with Widespread Virulence Properties 95
5 Chaperonin 60 Paralogs in Mycobacterium tuberculosis and Tubercle Formation 97
Brian Henderson
5.1 Introduction 97
5.2 Tuberculosis and the Tuberculoid Granuloma 97
5.3 Mycobacterial Factors Responsible for Granuloma Formation 98
5.4 Mycobacterium tuberculosis Chaperonin 60 Proteins, Macrophage Function, and Granuloma Formation 100
5.4.1 Mycobacterium tuberculosis has Two Chaperonin 60 Proteins 100
5.4.2 Moonlighting Actions of Mycobacterial Chaperonin 60 Proteins 101
5.4.3 Actions of Mycobacterial Chaperonin 60 Proteins Compatible with the Pathology of Tuberculosis 102
5.4.4 Identification of the Myeloid‐Cell‐Activating Site in M. tuberculosis Chaperonin 60.1 105
5.5 Conclusions 106
References 106
6 Legionella pneumophila Chaperonin 60, an Extra‐ and Intra‐Cellular Moonlighting Virulence‐Related Factor 111
Karla N. Valenzuela‐Valderas, Angela L. Riveroll, Peter Robertson, Lois E. Murray, and Rafael A. Garduno
6.1 Background 111
6.2 HtpB is an Essential Chaperonin with Protein‐folding Activity 112
6.3 Experimental Approaches to Elucidate the Functional Mechanisms of HtpB 112
6.3.1 The Intracellular Signaling Mechanism of HtpB in Yeast 113
6.3.2 Yeast Two‐Hybrid Screens 118
6.4 Secretion Mechanisms Potentially Responsible for Transporting HtpB to Extracytoplasmic Locations 120
6.4.1 Ability of GroEL and HtpB to Associate with Membranes 121
6.4.2 Ongoing Mechanistic Investigations on Chaperonins Secretion 122
6.5 Identifying Functionally Important Amino Acid Positions in HtpB 124
6.5.1 Site‐Directed Mutagenesis 125
6.6 Functional Evolution of HtpB 126
6.7 Concluding Remarks 127
References 129
Part 3.2 Peptidylprolyl Isomerases, Bacterial Virulence, and Targets for Therapy 135
7 An Overview of Peptidylprolyl Isomerases (PPIs) in Bacterial Virulence 137
Brian Henderson
7.1 Introduction 137
7.2 Proline and PPIs 137
7.3 Host PPIs and Responses to Bacteria and Bacterial Toxins 138
7.4 Bacterial PPIs as Virulence Factors 138
7.4.1 Proposed Mechanism of Virulence of Legionella pneumophila Mip 140
7.5 Other Bacterial PPIs Involved in Virulence 140
7.6 Conclusions 142
References 142
Part 3.3 Glyceraldehyde 3‐Phosphate Dehydrogenase (GAPDH): A Multifunctional Virulence Factor 147
8 GAPDH: A Multifunctional Moonlighting Protein in Eukaryotes and Prokaryotes 149
Michael A. Sirover
8.1 Introduction 149
8.2 GAPDH Membrane Function and Bacterial Virulence 150
8.2.1 Bacterial GAPDH Virulence 151
8.2.2 GAPDH and Iron Metabolism in Bacterial Virulence 153
8.3 Role of Nitric Oxide in GAPDH Bacterial Virulence 153
8.3.1 Nitric Oxide in Bacterial Virulence: Evasion of the Immune Response 154
8.3.2 Formation of GAPDHcys‐NO by Bacterial NO Synthases 155
8.3.3 GAPDHcys‐NO in Bacterial Virulence: Induction of Macrophage Apoptosis 155
8.3.4 GAPDHcys‐NO in Bacterial Virulence: Inhibition of Macrophage iNOS Activity 156
8.3.5 GAPDHcys‐NO in Bacterial Virulence: Transnitrosylation to Acceptor Proteins 157
8.4 GAPDH Control of Gene Expression and Bacterial Virulence 158
8.4.1 Bacterial GAPDH Virulence 159
8.5 Discussion 160
Acknowledgements 162
References 162
9 Streptococcus pyogenes GAPDH: A Cell‐Surface Major Virulence Determinant 169
Vijay Pancholi
9.1 Introduction and Early Discovery 169
9.2 GAS GAPDH: A Major Surface Protein with Multiple Binding Activities 170
9.3 AutoADP‐Ribosylation of SDH and Other Post‐Translational Modifications 172
9.4 Implications of the Binding of SDH to Mammalian Proteins for Cell Signaling and Virulence Mechanisms 173
9.5 Surface Export of SDH/GAPDH: A Cause or Effect? 178
9.6 SDH: The GAS Virulence Factor‐Regulating Virulence Factor 180
9.7 Concluding Remarks and Future Perspectives 183
References 183
10 Group B Streptococcus GAPDH and Immune Evasion 195
Paula Ferreira and Patrick Trieu‐Cuot
10.1 The Bacterium GBS 195
10.2 Neonates are More Susceptible to GBS Infection than Adults 195
10.3 IL‐10 Production Facilitates Bacterial Infection 196
10.4 GBS Glyceraldehyde‐3‐Phosphate Dehydrogenase Induces IL‐10 Production 197
10.5 Summary 199
References 200
11 Mycobacterium tuberculosis Cell‐Surface GAPDH Functions as a Transferrin Receptor 205
Vishant M. Boradia, Manoj Raje, and Chaaya Iyengar Raje
11.1 Introduction 205
11.2 Iron Acquisition by Bacteria 206
11.2.1 Heme Uptake 206
11.2.2 Siderophore‐Mediated Uptake 207
11.2.3 Transferrin Iron Acquisition 207
11.3 Iron Acquisition by Intracellular Pathogens 207
11.4 Iron Acquisition by M. tb 208
11.4.1 Heme Uptake 208
11.4.2 Siderophore‐Mediated Iron Acquisition 209
11.4.3 Transferrin‐Mediated Iron Acquisition 209
11.5 Glyceraldehyde‐3‐Phosphate Dehydrogenase (GAPDH) 210
11.6 Macrophage GAPDH and Iron Uptake 210
11.6.1 Regulation 210
11.6.2 Mechanism of Iron Uptake and Efflux 211
11.6.3 Role of Post‐Translational Modifications 211
11.7 Mycobacterial GAPDH and Iron Uptake 212
11.7.1 Regulation 212
11.7.2 Mechanism of Iron Uptake 215
11.7.3 Uptake by Intraphagosomal M. tb 216
11.8 Conclusions and Future Perspectives 216
Acknowledgements 218
References 219
12 GAPDH and Probiotic Organisms 225
Hideki Kinoshita
12.1 Introduction 225
12.2 Probiotics and Safety 225
12.3 Potential Risk of Probiotics 227
12.4 Plasminogen Binding and Enhancement of its Activation 228
12.5 GAPDH as an Adhesin 229
12.6 Binding Regions 232
12.7 Mechanisms of Secretion and Surface Localization 234
12.8 Other Functions 235
12.9 Conclusion 236
References 237
Part 3.4 Cell‐Surface Enolase: A Complex Virulence Factor 245
13 Impact of Streptococcal Enolase in Virulence 247
Marcus Fulde and Simone Bergmann
13.1 Introduction 247
13.2 General Characteristics 248
13.3 Expression and Surface Exposition of Enolase 249
13.4 Streptococcal Enolase as Adhesion Cofactor 252
13.4.1 Enolase as Plasminogen‐Binding Protein 252
13.4.1.1 Plasminogen‐Binding Sites of Streptococcal Enolases 253
13.4.2 Role of Enolase in Plasminogen‐Mediated Bacterial‐Host Cell Adhesion and Internalization 254
13.4.3 Enolase as Plasminogen‐Binding Protein in Non‐Pathogenic Bacteria 255
13.5 Enolase as Pro‐Fibrinolytic Cofactor 256
13.5.1 Degradation of Fibrin Thrombi and Components of the Extracellular Matrix 257
13.6 Streptococcal Enolase as Cariogenic Factor in Dental Disease 258
13.7 Conclusion 258
Acknowledgement 259
References 259
14 Streptococcal Enolase and Immune Evasion 269
Masaya Yamaguchi and Shigetada Kawabata
14.1 Introduction 269
14.2 Localization and Crystal Structure 271
14.3 Multiple Binding Activities of α‐Enolase 273
14.4 Involvement of α‐Enolase in Gene Expression Regulation 276
14.5 Role of Anti‐α‐Enolase Antibodies in Host Immunity 277
14.6 α‐Enolase as Potential Therapeutic Target 279
14.7 Questions Concerning α‐Enolase 281
References 281
15 Borrelia burgdorferi Enolase and Plasminogen Binding 291
Catherine A. Brissette
15.1 Introduction to Lyme Disease 291
15.2 Life Cycle 292
15.3 Borrelia Virulence Factors 292
15.4 Plasminogen Binding by Bacteria 293
15.5 B. burgdorferi and Plasminogen Binding 294
15.6 Enolase 295
15.7 B. burgdorferi Enolase and Plasminogen Binding 297
15.8 Concluding Thoughts 301
Acknowledgements 301
References 301
Part 3.5 Other Glycolytic Enzymes Acting as Virulence Factors 309
16 Triosephosphate Isomerase from Staphylococcus aureus and Plasminogen Receptors on Microbial Pathogens 311
Reiko Ikeda and Tomoe Ichikawa
16.1 Introduction 311
16.2 Identification of Triosephosphate Isomerase on S. aureus
as a Molecule that Binds to the Pathogenic Yeast C. neoformans 312
16.2.1 Co‐Cultivation of S. aureus and C. neoformans 312
16.2.2 Identification of Adhesins on S. aureus and C. neoformans 312
16.2.3 Mechanisms of C. neoformans Cell Death 313
16.3 Binding of Triosephosphate Isomerase with Human Plasminogen 314
16.4 Plasminogen‐Binding Proteins on Trichosporon asahii 314
16.5 Plasminogen Receptors on C. neoformans 316
16.6 Conclusions 316
References 317
17 Moonlighting Functions of Bacterial Fructose 1,6‐Bisphosphate Aldolases 321
Neil J. Oldfield, Fariza Shams, Karl G. Wooldridge, and David P.J. Turner
17.1 Introduction 321
17.2 Fructose 1,6‐bisphosphate Aldolase in Metabolism 321
17.3 Surface Localization of Streptococcal Fructose 1,6‐bisphosphate Aldolases 322
17.4 Pneumococcal FBA Adhesin Binds Flamingo Cadherin Receptor 323
17.5 FBA is Required for Optimal Meningococcal Adhesion to Human Cells 324
17.6 Mycobacterium tuberculosis FBA Binds Human Plasminogen 325
17.7 Other Examples of FBAs with Possible Roles in Pathogenesis 326
17.8 Conclusions 327
References 327
Part 3.6 Other Metabolic Enzymes Functioning in Bacterial Virulence 333
18 Pyruvate Dehydrogenase Subunit B and Plasminogen Binding in Mycoplasma 335
Anne Gründel, Kathleen Friedrich, Melanie Pfeiffer, Enno Jacobs, and Roger Dumke
18.1 Introduction 335
18.2 Binding of Human Plasminogen to M. pneumoniae 337
18.3 Localization of PDHB on the Surface of M. pneumoniae Cells 340
18.4 Conclusions 343
References 344
Part 3.7 Miscellaneous Bacterial Moonlighting Virulence Proteins 349
19 Unexpected Interactions of Leptospiral Ef‐Tu and Enolase 351
Natália Salazar and Angela Barbosa
19.1 Leptospira –Host Interactions 351
19.2 Leptospira Ef‐Tu 352
19.3 Leptospira Enolase 353
19.4 Conclusions 354
References 354
20 Mycobacterium tuberculosis Antigen 85 Family Proteins: Mycolyl Transferases and Matrix‐Binding Adhesins 357
Christopher P. Ptak, Chih‐Jung Kuo, and Yung‐Fu Chang
20.1 Introduction 357
20.2 Identification of Antigen 85 358
20.3 Antigen 85 Family Proteins: Mycolyl Transferases 359
20.3.1 Role of the Mycomembrane 359
20.3.2 Ag85 Family of Homologous Proteins 359
20.3.3 Inhibition and Knockouts of Ag85 360
20.4 Antigen 85 Family Proteins: Matrix‐Binding Adhesins 361
20.4.1 Abundance and Location 361
20.4.2 Ag85 a Fibronectin‐Binding Adhesin 362
20.4.3 Ag85 an Elastin‐Binding Adhesin 363
20.4.4 Implication in Disease 364
20.5 Conclusion 365
Acknowledgement 365
References 365
Part 3.8 Bacterial Moonlighting Proteins that Function as Cytokine Binders/Receptors 371
21 Miscellaneous IL‐1β‐Binding Proteins of Aggregatibacter actinomycetemcomitans 373
Riikka Ihalin
21.1 Introduction 373
21.2 A. actinomycetemcomitans Biofilms Sequester IL‐1β 374
21.3 A. actinomycetemcomitans Cells Take in IL‐1β 375
21.3.1 Novel Outer Membrane Lipoprotein of A. actinomycetemcomitans Binds IL‐1β 375
21.3.2 IL‐1β Localizes to the Cytosolic Face of the Inner Membrane and in the Nucleoids of A. actinomycetemcomitans 377
21.3.3 Inner Membrane Protein ATP Synthase Subunit β Binds IL‐1β 377
21.3.4 DNA‐Binding Histone‐Like Protein HU Interacts with IL‐1β 378
21.4 The Potential Effects of IL‐1β on A. actinomycetemcomitans 379
21.4.1 Biofilm Amount Increases and Metabolic Activity Decreases 379
21.4.2 Potential Changes in Gene Expression 380
21.5 Conclusions 381
References 382
Part 3.9 Moonlighting Outside of the Box 387
22 Bacteriophage Moonlighting Proteins in the Control of Bacterial Pathogenicity 389
Janine Z. Bowring, Alberto Marina, José R. Penadés, and Nuria Quiles‐Puchalt
22.1 Introduction 389
22.2 Bacteriophage T4 I‐TevI Homing Endonuclease Functions as a Transcriptional Autorepressor 391
22.3 Capsid Psu Protein of Bacteriophage P4 Functions as a Rho Transcription Antiterminator 394
22.4 Bacteriophage Lytic Enzymes Moonlight as Structural Proteins 398
22.5 Moonlighting Bacteriophage Proteins De‐Repressing Phage‐Inducible Chromosomal Islands 398
22.6 dUTPase, a Metabolic Enzyme with a Moonlighting Signalling Role 401
22.7 Escherichia coli Thioredoxin Protein Moonlights with T7 DNA Polymerase for Enhanced T7 DNA Replication 404
22.8 Discussion 404
References 406
23 Viral Entry Glycoproteins and Viral Immune Evasion 413
Jonathan D. Cook and Jeffrey E. Lee
23.1 Introduction 413
23.2 Enveloped Viral Entry 414
23.3 Moonlighting Activities of Viral Entry Glycoproteins 415
23.3.1 Viral Entry Glycoproteins Moonlighting as Evasins 416
23.3.2 Evading the Complement System 417
23.3.3 Evading Antibody Surveillance 419
23.3.3.1 The Viral Glycan Shield 419
23.3.3.2 Shed Viral Glycoproteins: An Antibody Decoy 421
23.3.3.3 Antigenic Variations in Viral Glycoproteins 421
23.3.3.4 Shed Viral Glycoproteins and Immune Signal Modulation 423
23.3.4 Evading Host Restriction Factors 423
23.3.5 Modulation of Other Immune Pathways 424
23.4 Viral Entry Proteins Moonlighting as Saboteurs of Cellular Pathways 427
23.4.1 Sabotaging Signal Transduction Cascades 427
23.4.2 Host Surface Protein Sabotage 428
23.5 Conclusions 429
References 429
Index 439
