Lysosomes E-Book
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- Herausgeber: John Wiley & Sons
- Kategorie: Wissenschaft und neue Technologien
- Sprache: Englisch
Discussing recent findings, up-to-date research, and novel strategies, the book integrates perspectives from pharmacology, toxicology, and biochemistry to illustrate the potential of lysosomes in drug discovery and development.
• Explores basic principles and properties of lysosomes that allow them to act as regulators of cell metabolism, therapeutic targets, and sites for activation of drug conjugates
• Discusses the role of lysosomes in metabolism, drug targeting, apoptosis, cancer, aging, inflammation, autophagy, metabolism, toxicity, and membrane repair
• Introduces new pathways in therapeutic development and new mechanisms in drug development
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Seitenzahl: 1158
Veröffentlichungsjahr: 2016
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Table of Contents
Cover
Title Page
Copyright
Preface
References
List of Contributors
Chapter 1: Lysosomes: An Introduction
1.1 Historical Background
References
Chapter 2: Lysosome Biogenesis and Autophagy
2.1 Introduction
2.2 Pathways to the Lysosomes
2.3 Fusion and Fission between the Endolysosomal and Autophagy Pathways
2.4 Diseases
2.5 Concluding Remarks
Acknowledgments
References
Chapter 3: Multivesicular Bodies: Roles in Intracellular and Intercellular Signaling
3.1 Introduction
3.2 Downregulation of Signaling by Sorting onto ILVs
3.3 Upregulation of Signaling by Sorting onto ILVs
3.4 Intercellular Signaling Dependent on Sorting onto ILVs
3.5 Conclusion
References
Chapter 4: Lysosomes and Mitophagy
4.1 Summary
4.2 Mitochondrial Significance
4.3 History of Mitophagy
4.4 Mechanisms of Mitophagy
4.5 Conclusion
Acknowledgments
References
Chapter 5: Lysosome Exocytosis and Membrane Repair
5.1 Introduction
5.2 Functions of Lysosome Exocytosis
5.3 Mechanisms of Lysosome Exocytosis
5.4 Conclusion
Acknowledgments
References
Chapter 6: Role of Lysosomes in Lipid Metabolism
6.1 Introduction
6.2 Endocytic Uptake of Lipoproteins
6.3 Lipid Metabolism in Late Endosomes and Lysosomes
6.4 Autophagy and Lysosomal Lipid Turnover
6.5 Lysosomal Lipid Hydrolysis and Metabolic Regulation
6.6 Summary
References
Chapter 7: TFEB, Master Regulator of Cellular Clearance
7.1 Lysosome
7.2 The Transcriptional Regulation of Lysosomal Function
7.3 TFEB Subcellular Regulation is Regulated by Its Phosphorylation
7.4 A Lysosome-to-Nucleus Signaling Mechanism
7.5 TFEB and Cellular Clearance in Human Disease
References
Chapter 8: Lysosomal Membrane Permeabilization in Cell Death
8.1 Introduction
8.2 Cell Death Modalities
8.3 Lysosomal Membrane Permeabilization (LMP) and Cell Death
8.4 Conclusion
Acknowledgments
References
Chapter 9: The Lysosome in Aging-Related Neurodegenerative Diseases
9.1 Introduction
9.2 Lysosome Function in Aging Organisms
9.3 Lysosomes and Diseases of Late Age Onset
9.4 Lysosomes in Aging-Related Neurodegenerative Diseases
9.5 Conclusion
Acknowledgments
References
Chapter 10: Lysosome and Cancer
10.1 Introduction
10.2 Lysosomal Function and Its Importance for Cancer Development and Progression
10.3 Cancer-Induced Changes in Lysosomal Function
10.4 Cancer-Induced Changes in Lysosome Composition
10.5 Molecular Changes Involving Lysosomal Integrity
10.6 Conclusion
References
Chapter 11: The Genetics of Sphingolipid Hydrolases and Sphingolipid Storage Diseases
11.1 Introduction and Overview
11.2 Acid Ceramidase Deficiency: Farber Disease
11.3 Acid Sphingomyelinase Deficiency: Types A and B Niemann–Pick Disease
11.4 Beta-Glucocerebrosidase Deficiency: Gaucher Disease
11.5 Galactocerebrosidase Deficiency: Krabbe Disease/Globoid Cell Leukodystrophy
11.6 Arylsulfatase a Deficiency: Metachromatic Leukodystrophy
11.7 Alpha-Galactosidase a Deficiency: Fabry Disease
11.8 Beta-Galactosidase Deficiency: GM1 Gangliosidosis
11.9 Hexosaminidase A and B Deficiency: GM2 Gangliosidoses
11.10 Sphingolipid Activator Proteins
References
Chapter 12: Lysosome-Related Organelles: Modifications of the Lysosome Paradigm
12.1 Differences Between LROs and Secretory Granules
12.2 Physiological Functions of LROs
12.3 LRO Biogenesis
12.4 LRO Motility, Docking, and Secretion
12.5 LROs and Immunity to Pathogens
12.6 Perspectives
Acknowledgments
References
Chapter 13: Autophagy Inhibition as a Strategy for Cancer Therapy
13.1 Stages and Steps of Autophagy
13.2 Induction of Autophagy
13.3 Studies in Mouse Models Unravel the Dual Roles of Autophagy in Tumor Biology
13.4 Clinical Studies on Autophagy's Dual Role in Tumorigenesis
13.5 Mouse Models Provide the Rationale for Autophagy Modulation in the Context of Cancer Therapy
13.6 Multiple Druggable Targets in the Autophagy Pathway
13.7 Overview of Preclinical Autophagy Inhibitors and Evidence Supporting Combination with Existing and New Anticancer Agents
13.8 Proximal Autophagy Inhibitors
13.9 Quinolines: From Antimalarials to Prototypical Distal Autophagy Inhibitors
13.10 Summary for the Clinical Trials for CQ/HCQ
13.11 Developing More Potent Anticancer Autophagy Inhibitors
13.12 Summary, Conclusion, and Future Directions
13.13 In Summary
References
Chapter 14: Autophagy Enhancers, are we there Yet?
14.1 Introduction
14.2 Autophagy Impairment and Diseases
14.3 Autophagy Enhancer Screening
14.4 Other Agents that Boost Autophagy and Lysosomal Functions
14.5 Concluding Remarks
References
Chapter 15: Pharmacological Chaperones as Potential Therapeutics for Lysosomal Storage Disorders: Preclinical Research to Clinical Studies
15.1 Introduction
15.2 Fabry Disease
15.3 Gaucher Disease
15.4 GM2 Gangliosidoses (Tay–Sachs/Sandhoff Diseases)
15.5 Pompe Disease
15.6 PC-ERT Combination Therapy
References
Chapter 16: Endosomal Escape Pathways for Delivery of Biologics
16.1 Introduction
16.2 Endosome Characteristics
16.3 Delivery of Nature's Biologics: Lessons on Endosomal Escape from Pathogens
16.4 Endosomal Escape Using Engineered Systems
16.5 Conclusion
References
Chapter 17: Lysosomes and Antibody–Drug Conjugates
17.1 Introduction
17.2 Receptor Internalization
17.3 Antibody–Drug Conjugates
17.4 Mechanisms of Resistance to ADCs
17.5 Summary
References
Chapter 18: The Mechanisms and Therapeutic Consequences of Amine-Containing Drug Sequestration in Lysosomes
18.1 Introduction
18.2 Lysosomal Trapping Overview
18.3 Techniques to Assess Lysosomal Trapping
18.4 Influence of Lysosomotropism on Drug Activity
18.5 Influence of Lysosomal Trapping on Pharmacokinetics
18.6 Pharmacokinetic Drug–Drug Interactions Involving Lysosomes
References
Chapter 19: Lysosome Dysfunction: an Emerging Mechanism of Xenobiotic-Induced Toxicity
19.1 Introduction
19.2 Compounds that Impact Lysosomal Function
19.3 Cellular Consequences
19.4 Impaired Lysosomal Function as a Mechanism for Organ Toxicity
19.5 Concluding Remarks
References
Chapter 20: Lysosomes and Phospholipidosis in Drug Development and Regulation
20.1 Introduction
20.2 FDA Involvement
20.3 Autophagy and DIPL
20.4 Early Experience with Lethal DIPL
20.5 Clinical and Nonclinical Expressions of DIPL
20.6 Physical Chemistry
20.7 Quantitative Structure–Activity Relationship (QSAR)
20.8 Toxicogenomics
20.9 Fluorescence, Dye, and Immunohistochemical Methods for Screening
20.10 FDA Database and QSAR Modeling
20.11 Linking Phospholipidosis and Overt Toxicity
20.12 Phospholipidosis and QT Interval Prolongation
20.13 DIPL Mechanisms
20.14 Treatment
20.15 Discussion
20.16 Future Directions and Recommendations
References
Index
End User License Agreement
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Guide
Cover
Table of Contents
preface
Begin Reading
List of Illustrations
Chapter 2: Lysosome Biogenesis and Autophagy
Figure 2.1 Schematic drawing depicting the endocytic and autophagy pathways to the lysosomes. ALR, autolysosome reformation; CMA, chaperone-mediated autophagy; ILV, intraluminal vesicle; MVB, multivesicular body; PAS, phagophore assembly site. (
See color plate section for the color representation of this figure.
)
Figure 2.2 Gallery of electron micrographs providing characteristic examples of endolysosomal compartments. From (a) to (d) a sequence of early-to-late endolysosomal intermediates is shown. Arrows in (a) and (b) point to the bilayered flat clathrin coat harboring protein machinery involved in intraluminal vesicle (ILV) formation. Early endosomes (EE) and late endosomes (LE) contain an increasing number of ILVs. Lysosomes (LY) show typical membrane lamella. Pictures were taken from distinct cell models: (a) embryonic zebrafish, (b) human prostate cancer (PC3) cell, (c) activated mouse B cell, (d) HeLa cell. ER, endoplasmic reticulum; M, mitochondrion; RE, recycling endosome. Bar = 200 nm. (a–c). Courtesy of Ann de Mazière, Department of Cell Biology, University Medical Center, Utrecht, The Netherlands.
Figure 2.3 Electron micrograph showing the three main intermediates of macroautophagy: phagophore, autophagosome and autolysosome. Picture taken from Akt knockdown human prostate cell (PC3) [41]. ER, endoplasmic reticulum. Bar = 200 nm.
Figure 2.4 Schematic overview of the distinct Atg complexes required for autophagy. The ULK and PtsIns3K complex and the ATG9 cycling system are key in the organization of the PAS and biogenesis of the phagophore. The two ubiquitin-like systems appear to be mostly involved into the elongation of the phagophore into an autophagosome. WIPIs is a protein family with four members, that is, WIPI1-4. LC3/ATG* is composed of six proteins: LC3A–C and GABARAPL1–3. There are also four isoforms of ATG4, that is, ATG4A–D.
Chapter 3: Multivesicular Bodies: Roles in Intracellular and Intercellular Signaling
Figure 3.1 Electron micrograph of an MVB. Hela cells were stimulated with EGF in the presence of anti-EGFR 10 nm gold conjugate and prepared for transmission electron microscopy. The image shows an MVB with EGFR (gold particles) localized on the ILVs. The MVB-containing discrete ILVs are readily distinguished from the electron-dense lysosome that contains characteristic multilamellar membranous whorls. Scale bar = 200 nm.
Figure 3.2 Downregulation of EGFR signaling by sorting onto ILVs. (a) EGFRs at the cell surface dimerize on ligand binding and are internalized into early endosomes where sorting of ligand–receptor complexes destined for lysosomal degradation onto ILVs begins (“early” MVBs). EGFR-containing ILVs accumulate in the maturing MVB and when all recycling proteins have been removed the “late” MVB fuses with the lysosome and the contents are degraded. (b) Signaling from the EGFR tyrosine kinase on the limiting membrane of the MVB is dampened by a combination of dephosphorylation and sequestration away from the cytosol on ILVs. Ubiquitination-dependent interaction with Hrs, and subsequent recruitment of the ESCRT machinery, concentrates EGFR on the MVB-limiting membrane where both the EGFR and ESCRTs can potentially interact with ER-localized PTP1B via direct membrane contacts between the ER and MVBs. ESCRTs then promote sequestration of EGFR on ILVs of MVBS, which ultimately fuse with the lysosome, ensuring signal termination. (
See color plate section for the color representation of this figure.
)
Figure 3.3 Upregulation of Wnt signaling by sorting onto ILVs. In resting cells, cytosolic β-catenin levels are kept low through the activity of an inhibitory complex that contains GSK3, which phosphorylates β-catenin, promoting its ubiquitination and proteosomal degradation. When Wnt ligands bind Frizzled receptors (Fz) and LRP coreceptors at the cell surface, a multiprotein complex is recruited that includes disheveled (Dvl), the scaffold protein, Axin, the kinases, CK1γ, and β-catenin ESCRT-dependent sequestration of the Wnt signaling complex onto the ILVs of MVBs prevents GSK3-mediated phosphorylation of newly synthesized β-catenin, allowing cytosolic β-catenin levels to rise, leading to its transport to the nucleus to activate transcription of Wnt target genes. The lack of sequestration of the Wnt signaling complex onto ILVs in the absence of Hrs renders GSK3 able to phosphorylate newly synthesized β-catenin, leading to ubiquitination and degradation, thus preventing β-catenin-mediated transcriptional activation in the nucleus. (
See color plate section for the color representation of this figure.
)
Figure 3.4 Intercellular Notch signaling mediated by ligand-bearing exosomes. Exosomes containing the Notch ligand, Delta, are released from the signal-sending cell and bind to Notch on the cell surface of the signal-receiving cell. Both Notch and Delta are endocytosed by the signal-receiving cell, but it is unclear how. In the left-hand panel, Delta-bearing exosomes fuse at the cell surface and then Delta and Notch on the same membrane are endocytosed. (i) Delta is selectively sorted onto the ILVs of MVBs where it can bind Notch on the MVB-limiting membrane. Conditions in the MVB may be favorable for S2 and then S3 cleavage releasing the Notch intracellular domain that can then traffic to the nucleus. (ii) Notch is selectively targeted to the ILV where it can bind Delta on the limiting membrane of the MVB. In this case, if S2 and S3 cleavage occurs, the intracellular domain of Notch would be sequestered within the ILV and would require back fusion of the ILV with the limiting membrane for release into the cytosol and traffic to the nucleus. (iii) Both Notch and Delta are sorted onto ILVs and this serves to target both proteins to the lysosome for degradation. In the right-hand panel, the exosomes are endocytosed forming an MVB where the limiting membrane is derived from the signal-receiving cell and the ILVs are derived from the signal-sending cell. In this case, Delta–Notch interactions could be continued after endocytosis. In all cases, the ultimate destination of the MVB in the signal-receiving cell that contains Delta and Notch, with or without the Notch intracellular domain, is likely to be the lysosome. (
See color plate section for the color representation of this figure.
)
Chapter 4: Lysosomes and Mitophagy
Figure 4.1 Summary of mitophagy in yeast and mammalian cells. Mitochondria require specific targeting signals to recruit the autophagic machinery and mediate autophagosome formation and lysosomal degradation. (
See color plate section for the color representation of this figure.
)
Chapter 5: Lysosome Exocytosis and Membrane Repair
Figure 5.1 Lysosome exocytosis is required for extracellular degradation. Electron micrograph of a macrophage digesting aggregated LDL, labeled with colloidal gold, sequestered in deep membrane invaginations (arrow). During atherogenesis, macrophages make an extracellular degradative compartment to catabolize aggregated LDL. Formation of the compartment is likely aided by extensive plasma membrane ruffling at contact sites (asterisks). Lysosomal enzymes are delivered to the contact area through exocytosis and the compartment is acidified by plasma membrane vacuolar ATPase, allowing activity of lysosomal enzymes. This process promotes extracellular degradation of aggregated LDL prior to uptake of partially digested material and ensuing foam cell formation. Portions of aggregated LDL that have not been sequestered by the macrophage can also be seen (arrowheads).
Figure 5.2 Schematic of mechanisms involved in lysosome exocytosis. Lysosomes acquire lysosomal hydrolases from late endosomes. Signaling through ligation of cell surface receptors induces microtubule-dependent movement of lysosomes toward the plasma membrane. Local depolymerization of cortical actin can promote docking of lysosomes at the plasma membrane in some systems. While in other cell types, tethering of lysosomes to cortical actin appears to be necessary for exocytosis to occur. Engagement of vesicular membrane-associated and target membrane-associated SNAREs occurs with the help of accessory proteins, such as calcium sensing synaptotagmins. The binding of SNAREs makes lysosome fusion with the plasma membrane more energetically favorable and influx of calcium stimulates exocytosis to occur. This releases lysosomal hydrolases and other secretory products into the extracellular environment where they mediate various effector functions. (
See color plate section for the color representation of this figure.
)
Chapter 6: Role of Lysosomes in Lipid Metabolism
Figure 6.1 Schematic diagram of lipoprotein and lipid droplet degradation by lysosomes. Low-density lipoproteins (LDLs) bind to receptors on the surface of cells and are rapidly internalized via clathrin-coated pits. The contents of the clathrin-coated pits are delivered to sorting endosomes, which are transient organelles with an internal pH of about 6.2. The low pH causes LDL to dissociate from its receptor, and the empty receptors are rapidly exported from the sorting endosome in narrow diameter tubules. The receptors return to the cell surface either directly or after passing through an intermediate organelle, the endocytic recycling compartment (ERC). The sorting endosomes mature into late endosomes, which are somewhat more acidic and have lysosomal enzymes that have been delivered from the trans-Golgi network. Membrane invaginations at the surface of the late endosomes create internal vesicles that are enriched in BMP. Lysosomal enzymes, which are activated by the low pH, and these digest the internalized LDL. Membrane lipids in the bilayer are mainly digested on the internal vesicles, which protects the limiting membrane against leakage. Lipid droplets can be surrounded by phagophores to create an autophagosome, which fuses with late endosomes or lysosomes to create a digestive autolysosome.
Chapter 7: TFEB, Master Regulator of Cellular Clearance
Figure 7.1 Central role of lysosomes in key cellular processes. (
See color plate section for the color representation of this figure.
)
Figure 7.2 Systems biology approach used to discover the CLEAR network. The clear network is inferred by integrating the coexpression analysis of microarray data and promoter analysis. Pattern discovery analysis of the promoter regions of the known lysosomal genes resulted in the identification of a palindromic 10-base preferentially located at 200 bp from the transcription start site. The CLEAR consensus sequence overlaps that of the E-box (CANNTG), a known target site for basic helix–loop–helix transcription factors. (
See color plate section for the color representation of this figure.
)
Figure 7.3 Model depicting Ca
2+
-mediated regulation of TFEB. This Figure illustrates how transcription factor TFEB is induced by starvation and mediates the starvation response. TFEB, in adequate nutrition condition, is phosphorylated by mTORC1 on the lysosomal surface. This keeps TFEB inactive by cytosolic sequestration. During starvation, mTORC1 is released from the lysosomal surface and becomes inactive while a calcium-dependent serine–threonine phosphatase, calcineurin, dephosphorylates TFEB. Thus, TFEB can no longer be phosphorylated by mTORC1 and its dephosphorylation promotes its nuclear translocation, where it induces its own transcription. Therefore, starvation regulates TFEB activity through a dual mechanism that involves a posttranslational modification (phosphorylation) and a transcriptional autoregulatory loop. Once in the nucleus, TFEB regulates the expression of genes involved in the lysosomal–autophagy pathway. (
See color plate section for the color representation of this figure.
)
Figure 7.4 TFEB activation on cellular mechanisms that lead to cellular clearance. TFEB controls lysosomal biogenesis, autophagosome biogenesis, autophagosome–lysosome fusion, and lysosomal exocytosis. The concerted action of these processes leads to cellular clearance. (
See color plate section for the color representation of this figure.
)
Figure 7.5 Diseases that respond to TFEB-mediated clearance. The major impact that TFEB has on cellular clearance identifies this pathway as a possible therapeutic target for a variety of diseases. (
See color plate section for the color representation of this figure.
)
Chapter 8: Lysosomal Membrane Permeabilization in Cell Death
Figure 8.1 Mechanisms of LMP.
Figure 8.2 Molecular events upstream and downstream of LMP. Most exogenous compounds cause LMP as a consequence of direct targeting of the lysosomal membrane or osmotic stability. In contrast, LMP can also occur in consequence of cell death signaling. The most likely factors that mediate LMP downstream of MOMP activation are ROS and increased intracellular calcium concentration linked to activation of several lipases, which collectively affect the osmotic stability of lysosomes. Downstream of LMP, the best-studied effector mechanism is the proteolytic activity of lysosomal cathepsins that translocate to the cytosol. In the case of moderate LMP, cell response is dominated by the proteolytic activation of BID and degradation of antiapoptotic BCL-2 proteins and caspase inhibitors. Extensive LMP can cause general proteolysis and thereby necrosis.
Figure 8.3 Lysosomal apoptotic pathway. Upon LMP, lysosomal cysteine cathepsins and aspartic cathepsin D can be translocated to the cytosol, where they promote apoptotic signaling upstream and downstream of MOMP by proteolytic activation of BID and degradation of antiapoptotic BCL-2 proteins and caspase inhibitor X-linked inhibitor of apoptosis (XIAP) (bold arrows). Truncated BID (tBID) transmits LMP to MOMP via recruitment of BAX and homooligomerization of BAX and BAK in the outer mitochondrial membrane (regular arrows) and/or sequestration of antiapoptotic BCL-2 proteins. Downstream of MOMP (light arrows), cytochrome c, which is translocated from the intermembrane space of mitochondria into the cytosol, mediates the assembly of the apoptosome, which serves as a platform for the activation of the initiator caspase-9. Caspase-9 then activates executioner caspases-3 and -7. Additional proapoptotic factors are translocated through the pores in the MOM, including SMAC/DIABLO that antagonizes and the serine protease HtrA2/Omi that degrades the inhibitors of apoptotic proteins (IAPs), thereby promoting caspase activity.
Chapter 9: The Lysosome in Aging-Related Neurodegenerative Diseases
Figure 9.1 Major routes of substrate delivery to lysosomes. (a) Macroautophagy is characterized by the sequestration of structures targeted for degradation into double-membrane vesicles called autophagosomes. Fully formed autophagosomes may first fuse with late endosomes to form an amphisome before fusion with hydrolase-filled lysosomes, which causes degradation of the inner limiting membrane releasing the hydrolases into the lumen of the created autolysosome. Introduction of a fully activated proton pump (V-ATPase) induces full acidification of the autolysosomal lumen necessary to activate acid hydrolases for optimal digestion of substrates. The resulting metabolites are transported into the cytoplasm and used for synthesis of new macromolecules or as a source of energy. (b) During chaperone-mediated autophagy, proteins carrying the pentapeptide KFERQ-like sequence are recognized by the Hsc70 chaperone, which then associates with the integral lysosome membrane protein LAMP-2A, triggering its oligomerization. This event leads to the translocation of the bound protein into the lysosome interior through a process that requires Hsc70. (c) Microautophagy involves “bulk” or chaperone-mediated internalization and degradation of cytoplasmic substrates into late endosome/MVB or lysosomal compartments by a process of membrane invagination followed by membrane scission to release the cargo into the lysosomal lumen for degradation. (d) Heterophagy involves the lysosomal degradation of plasma membrane components and exogenous substrates after they are internalized by bulk or receptor-mediated endocytosis. After selected proteins are sorted to different cellular destinations or recycled to the plasma membrane, proteins targeted for degradation are trafficked to late endosomes/MVB, which fuse with a lysosome or with autophagosomes to effect degradation. (
See color plate section for the color representation of this figure.
)
Figure 9.2 Genetic evidence strongly implicates the lysosomal network in the pathogenesis of neurodegenerative disease. The diagram identifies selected neurological disorders in which the pathogenic gene encodes a protein that plays a vital role in lysosomal network functioning. Mutations of the indicated genes are causative for familial forms of each disease and have also been shown to disrupt lysosomal function directly or through malfunctions of another compartment in the lysosomal network. Because of an extensive cross-talk among vesicular compartments comprising the lysosomal network, a defect in any component of the various pathways to lysosomes can potentially impede the efficiency of lysosomal digestion and signaling. (
See color plate section for the color representation of this figure.
)
Chapter 10: Lysosome and Cancer
Figure 10.1 Cancer development induces changes in the lysosomal function. Normal, healthy cells undergo dramatic changes that affect their lysosomal function upon transformation to cancer cells. Cancer development and progression induces lysosomal biogenesis increasing the expression of various lysosomal hydrolases (gray). It alters the lysosomal membrane integrity, sensitizing them to LMP and lysosomal leakage that can lead to LCD. It additionally increases the size of lysosomes and alters their distribution in a manner where normally mostly perinuclear lysosomes adapt pericellular locations close to the invasive cellular protrusions at the cell membrane, which allows them to secrete or exocytose their hydrolytic contents by a process called “lysosomal exocytosis.” Upon reaching the extracellular space, lysosomal hydrolases can induce cell growth, extracellular matrix degradation, invasion, angiogenesis, and extracellular acidification. (
See color plate section for the color representation of this figure.
)
Figure 10.2 Cancer induces changes in lysosomal composition. These include changes in the expression levels and activity of several lysosomal hydrolases. Some of these changes are “protumor” processes contributing to tumor growth, invasion, metastasis, and drug resistance, and some of them are “antitumor” processes that sensitize lysosomes to LMP and LCD. (
See color plate section for the color representation of this figure.
)
Figure 10.3 Lysosomal sphingolipid catabolism. Sphingomyelin is an abundant structural lipid of biological membranes. Acid sphingomyelinase catalyzes sphingomyelin into ceramide, which is a membrane lipid that can be associated with lipid rafts and function as a signaling molecule regulating cell death and autophagy. Acid ceramidase converts ceramide into sphingosine, which is a soluble detergent that can also function as a signaling molecule. Finally, sphingosine kinase phosphorylates sphingosine turning it into sphingosine-1-phosphate, a soluble signaling molecule that can bind to cell surface receptor promoting cell survival and autophagy.
Chapter 12: Lysosome-Related Organelles: Modifications of the Lysosome Paradigm
Figure 12.1 Examples of LRO ultrastructure. Shown are transmission electron micrographs (courtesy of G. Raposo, Insitut Curie and CNRS, Paris, France) of a few LROs described in this chapter. (a) Melanosomes in a human melanoma cell line; (b) azurophilic granules from an eosinophil; (c) cytolytic granules in a cytotoxic T cell; (d) MIIC from dendritic cells (immunogold labeled for MHC-II); (e) a Weibel–Palade body in a human umbilical vein endothelial cell.
Figure 12.2 Model for biogenesis of four vertebrate LROs. Shown are models for the biogenesis of immature (iMel) and mature (mMel) melanosomes (left, brown and gold), platelet α granules (pink), lysosomes (violet), CTL LGs (gray), and WPBs (right, blue) relative to endosomal and biosynthetic organelles. Golgi,
trans
-Golgi network (TGN), early endosomes, late endosomes/multivesicular bodies (MVBs), and lysosomes are indicated. Key cargo molecules discussed in the text are noted in the same color as the LRO, and effectors involved in biogenetic steps are labeled in black text. Arrows indicate relevant trafficking pathways. Left, immature melanosomes (iMel) emerge from vacuolar domains of early endosomes, and mature by cargo delivery from tubulovesicular domains of early endosomes through AP-1-coated or AP-3-coated vesicles; recycling endosomal domains associated with KIF13A and AP-1 migrate along microtubules toward maturing melanosomes for delivery of some cargoes as indicated. BLOC-1 facilitates tubule-mediated transport; BLOC-2, BLOC-3, RAB32, and RAB38 likely function downstream. Center left, platelet α granules derive in an NBEAL2-dependent process from late endosomes within megakaryocytes, and receive both biosynthetic and endocytic cargoes. Late endosomes in the same cells also fuse with lysosomes to deliver other cargoes. Center right, in CTLs and NK cells, immature LGs (iLGs) also derive by fusion of late endosomes with dense core structures containing perforin and granzymes. iLGs then fuse with recycling endosome-derived structures upon stimulation by target cells to form mature LGs (mLGs). MUNC13-4 controls the fusion of RAB11-containing exocytic compartments with RAB27A-containing iLG in a process that does not require a physical interaction between MUNC13-4 and RAB27A. In the final step, MUNC13-4 and RAB27A cooperate in the docking of lytic granules to the plasma membrane, to allow for granule content secretion. Right, vWF forms long fibrous polymers in the TGN of endothelial cells. Nascent immature WPBs (iWPBs) then bud off from the TGN encasing the vWF fibers likely with membrane cargoes such as P-selectin. Other cargoes, such as CD63, are then delivered from early endosomes in an AP-3-dependent manner. Marks et al. [24]. Copyright 2013, Reproduced with permission of Elsevier. (
See color plate section for the color representation of this figure.
)
Figure 12.3 Model for LRO function in conventional DCs and pDCs. Left, LROs and phagosome maturation in DCs. 1. Antigens captured by endocytosis or macropinocytosis enter the endolysosomal system and are degraded to smaller peptides. Peptides encounter MHC-II molecules as endosomes mature to late endosomes/MIICs and lysosomes. Antigen loading mostly occurs within late endosomes/MIICs and lysosomes that are enriched in the regulatory component HLA-DM. From these compartments, peptide-loaded MHC-II molecules are delivered to the cell surface (black straight arrow) for presentation to T cells. 2. Particulate antigens captured by phagocytosis are degraded in phagosomes as the phagosomes mature. Maturation is achieved by the acquisition of content (including MHC-II) from early and late endosomes/MIICs and lysosomes by both direct fusion (open arrows) and vesicular transport (turquoise arrows; dashed arrows indicate possible pathways for MHC-II transport that are not yet confirmed). Antigen is loaded onto MHC-II predominantly in late phagosomes. Phagosome maturation is supported by autophagy (ATG; light violet) proteins, which might derive from autophagosomes themselves or independently from the cytosol, and by signaling from pattern recognition receptors (PRRs, black arrow) such as TLRs. PRRs such as TLR4 are delivered to phagosomes from early endosomes in an AP-3-dependent manner (mauve dashed arrow). From late phagosomes, peptide-loaded MHC-II is delivered to the cell surface either directly (not shown) or via an intermediate tubular MHC-II storage compartment for presentation to T cells (black straight arrow). Delivery to or from this compartment appears to be regulated by PRR signaling from the phagosome (dashed black arrows). Right, IRF7 LROs and type I IFN signaling in pDCs. TLR9 is trafficked from the biosynthetic pathway to VAMP-3-positive early endosomes. Here TLR9 is cleaved and becomes competent for signaling to activate proinflammatory cytokine expression through NF-κB (NF-κB endosome). Cleaved TLR9 is then targeted in an AP-3-dependent manner to a LAMP2-positive LRO (IRF7 LRO) harboring the adaptor TRAF3. Here TLR9 signals through IRF7 to induce the transcription of type-1 interferon genes. Adapted from Traffic 14:135–152, Mantegazza AR, Magalhaes JG, Amigorena S, Marks MS, Presentation of phagocytosed antigen by MHC class I and II, 2013 and from Science 329:1530–1534, Sasai M, Linehan MM, Iwasaki A, Bifurcation of toll-like receptor 9 signaling by adaptor protein 3, 2010. (
See color plate section for the color representation of this figure.
)
Chapter 13: Autophagy Inhibition as a Strategy for Cancer Therapy
Figure 13.1 Molecular signaling of macroautophagy.
Figure 13.2 Chloroquine and Lys-series autophagy inhibitors.
Chapter 14: Autophagy Enhancers, are we there Yet?
Figure 14.1 Correlation of physicochemical properties with autophagy screening: A scatter plot showing the distribution of autophagy enhancers within the
c
log
P
-basic p
K
a
physicochemical property space. A group of compounds clustered within the area (blue dotted square) where the
c
log
P
was >2 and basic p
K
a
was greater than 6. (
See color plate section for the color representation of this figure.
)
Chapter 16: Endosomal Escape Pathways for Delivery of Biologics
Figure 16.1 Endosomal escape pathways. Delivery of macromolecular biologic drugs to the cytosol requires passage across at least one membrane barrier. The endosome membrane represents a convenient point of transit to the cytosol due to the fact that the characteristic, rapid acidification of the endosome provides a useful environmental trigger to deploy molecules that might otherwise be cytotoxic. At the same time, the endosome is a confined space where the environment can be manipulated and close apposition to the membrane is guaranteed. (a) Rupture of the endosomal membrane can be accomplished by membrane-lytic molecules such as amphipathic helices that display a series of positively charged R groups on one side of the helix facilitating interaction with negatively charged lipid head groups. The resulting disruption to the lipid bilayer can result in pore formation or larger fissures, sufficient to release endosomal contents to the cytosol including viral particles with a diameter up to 80 nm and bacteria with short-axis diameters up to 0.5 µm. The amphipathic helices are potentially cytotoxic and, thus, are stored in an inactive form as part of either the capsid (e.g., adenovirus), in the membrane of an enveloped virus (e.g., influenza virus), or within a bacterium (e.g.,
Listeria
). Typically, the deployment of helices is linked to acidification of the endosome and activation of either a viral protease, such as the L3/p23 protease of adenovirus, or an endosomal protease as in the case of influenza virus HA2 or listeriolysin O. When an enveloped virus utilizes a pH-triggered insertion of an amphipathic helix into the endosomal membrane, the insertion can be coupled with a conformational change in the helix-bearing membrane protein to enhance the fusion of the viral membrane and the endosomal membrane. (b) Endosomal membrane rupture can also be accomplished by osmotic lysis via the proton sponge effect. The formation of a particle that includes a high concentration of functional groups that convert from neutral to proton-accepting moieties at slightly acidic pH, for example, secondary or tertiary amino groups, results in fixation of protons in association with weak bases inside of the endosome. As a result, far more protons are pumped into the endosome to achieve a drop in pH. The massive influx of protons is accompanied by chloride counterions resulting in a locally high osmolarity. An influx of water by osmosis then elevates the interior pressure in the endosome resulting in lysis of the membrane. The high transfection efficiency of polyethylenimine (PEI) has been attributed to the proton sponge effect. Other weak bases such as histidine residues can also generate osmotic lysis of endosomes. (c) Membrane fusion can also contribute to the delivery of biologics to the cytosol across the endosomal membrane. Membrane fusion occurs when using cationic liposomes or lipoplexes due to the locally high number of positive charges in close apposition to the inner leaflet of the endosomal membrane. While acidification is not required for fusion to occur, the close association of membranes that occurs within the endosome is likely to favor fusion.
Chapter 17: Lysosomes and Antibody–Drug Conjugates
Figure 17.1 Internalization pathways mediating ADC uptake. (a) Clathrin-mediated endocytosis (CME) originates with adaptor proteins targeting receptors for internalization by forming clathrin-coated vesicles (CCVs), followed by membrane rearrangement and the formation of intracellular vesicles. These intracellular vesicles are released and fuse to form the early endosome. (b) Caveolae-mediated endocytosis is initiated by caveolae, a lipid raft containing sphingolipids, cholesterol, and caveolin proteins. Cargoes contained in caveolin-coated vesicles traffic to the caveosome, an intermediate compartment,
en route
to the early endosome. (c) Macropinocytosis mediates nonspecific uptake of soluble antigens. Intake is an actin-dependent process mediated by plasma membrane projections that give rise to macropinosomes, large endocytic vesicles (>1 µm). (
See color plate section for the color representation of this figure.
)
Figure 17.2 ADC receptor-mediated internalization. (1) The ADC binds to the antigen on the plasma membrane, then the complex internalizes into the early endosome. (2) The ADC/antigen complex navigates through vesicle maturation from the early endosome into the LE, where the pH is reduced from 6 to 5. (3) The ADC can then be delivered to the lysosome, where the pH is further reduced to 4, eventually targeted for degradation. (4) Alternatively, the ADC can release its antigen and recycle back to the cell surface. (
See color plate section for the color representation of this figure.
)
Figure 17.3 ADC structure. Antibody–monoclonal antibody (mAb) that specifically targets tumor-associated cell surface antigens. Linker – attaches and stabilizes payload to the mAb, releases cytotoxic payload within the target cell. Cytotoxic payload – highly potent cytotoxic agent. For example, those causing DNA damage or microtubule disruption. (
See color plate section for the color representation of this figure.
)
Chapter 18: The Mechanisms and Therapeutic Consequences of Amine-Containing Drug Sequestration in Lysosomes
Figure 18.1 Structures of neutral red and acridine orange, which are early examples of lysosomal vital stains.
Figure 18.2 Diagram illustrating the pH partitioning-based mechanism for accumulation of weakly basic drugs (B) in the acidic lysosomes. The equation at the bottom of the Figure represents the lysosome to extracellular space steady-state concentration ratio for a base. The dissociation constant for the conjugate acid of the weak base is denoted as
K
a
and [H
+
] is the proton concentration (subscript E represents extracellular and L represents lysosomal). The ratio of permeabilities of the ionized base to that of the unionized base in the lysosomal lipid bilayer is denoted by the α term.
Figure 18.3 Theoretical relationship between weak base p
K
a
and the alpha permeability parameter. The relationships were derived using the equation shown in Figure 18.2, with indicated values for alpha.
Figure 18.4 Structures of lysosomotropic antimalarial drugs chloroquine, mefloquine, and quinine.
Figure 18.5 Example of lysosomotropic detergent investigated by Firestone and colleagues.
Figure 18.6 (a) Diagram of proposed lysosomal proton transfer mechanism. (b) Structure of lysosomotropic proton transfer reagent.
Figure 18.7 Overview of intracellular distribution-based anticancer drug targeting platform. (
See color plate section for the color representation of this figure.
)
Figure 18.8 Hypothetical example illustrating the potential influence of lysosomotropism on the apparent volume of distribution of a drug. See text for details.
Chapter 19: Lysosome Dysfunction: an Emerging Mechanism of Xenobiotic-Induced Toxicity
Figure 19.1 Property distribution of approved drugs. A scatter plot showing the distribution of approved (including withdrawn ones) small molecules drugs within the
c
log
P
-basic p
K
a
physicochemical property space. Basic (basic p
K
a
> 6) and lipophilic (
c
log
P
> 1.5) drugs are in red circles.
Figure 19.2 Biological impacts of the lysosomotropic compounds. Compounds can perturb lysosome functions either by accumulation inside the lysosomes or direct inhibition of various lysosomal functions (e.g., decrease of lysosomal enzyme activity). Lysosomal membrane permeabilization can trigger cell death. In addition, lysosomal dysfunction can tamper membrane trafficking pathways including autophagy, endocytosis, phagocytosis, and exocytosis. Multiple signal transduction processes including MTORC, ERK1, Nrf2, and NFκB can also be modulated by lysosomal dysfunction due to the increase of p62 abundance resulting from autophagy deficiency. (
See color plate section for the color representation of this figure.
)
Chapter 20: Lysosomes and Phospholipidosis in Drug Development and Regulation
Figure 20.1 Comparison of dog (42 studies) and rat (134 studies) tissue distributions of drug-induced phospholipidosis from investigational new drug (IND) and new drug application (NDA) submissions to the USFDA from pharmaceutical companies [38]. GI, gastrointestinal; PLD, phospholipidosis. (
See color plate section for the color representation of this figure.
)
Figure 20.2 Relation between lowest observed drug-induced phospholipidosis (DIPL) dose and the lowest observed adverse effect level (LOAEL) toxicity dose in nonclinical studies submitted to the USFDA by pharmaceutical companies. A total 53 different studies were used to generate the graph [38]. LOEL, lowest observed effect level; PLD, phospholipidosis.
Figure 20.3 Relation between phospholipidosis, QT prolongation, protein trafficking effects, and adverse events. The QT-only group had adverse events that were significant but on target (i.e., related to the mechanism of action of drugs). The phospholipidosis-only group had mild adverse events. The overlap groups had significant, off-target adverse events associated with their use [38]. (
See color plate section for the color representation of this figure.
)
Figure 20.4 Flow chart for pharmaceutical development. When drug-induced phospholipidosis (DIPL) is predicted from
in silico
studies or
in vitro
assays, animal studies are used to evaluate DIPL. When DIPL is confirmed, it may be monitored with BMP and associated with tissue toxicity that may or may not be reversible. The BMP may be monitored clinically to assess potential drug toxicities.
List of Tables
Chapter 5: Lysosome Exocytosis and Membrane Repair
Table 5.1 Summary of Secretion Machinery Used by Different Cell Types for Exocytosis of Various Secretory Organelles
Chapter 11: The Genetics of Sphingolipid Hydrolases and Sphingolipid Storage Diseases
Table 11.1 Genetics of Human Sphingolipid Hydrolases and Diseases
Chapter 12: Lysosome-Related Organelles: Modifications of the Lysosome Paradigm
Table 12.1 LROs and Their Host Cells, Functions, and Cargoes
Chapter 13: Autophagy Inhibition as a Strategy for Cancer Therapy
Table 13.1 Yeast Autophagy Genes and Mammalian Homologs
Table 13.2 Mouse Model of Cancers with Genetically Manipulated Autophagy
Table 13.3 Preclinical Studies Supporting Autophagy Inhibition in Cancer Treatment
Table 13.4 Completed Clinical Trials for HCQ
Chapter 14: Autophagy Enhancers, are we there Yet?
Table 14.1 List of Autophagy Enhancers Reported in the Literature
Table 14.2 Comparable Biological Effects from mTOR Inhibitor (Autophagy Enhancer) and Lysosomotropic Compounds (Autophagy Inhibitor)
Chapter 16: Endosomal Escape Pathways for Delivery of Biologics
Table 16.1 Examples of Natural or Engineered Endosomal Escape for Delivery of Biologics to the Cytosol
Chapter 19: Lysosome Dysfunction: an Emerging Mechanism of Xenobiotic-Induced Toxicity
Table 19.1 Basic Compounds in Multiple Drug Classes
Chapter 20: Lysosomes and Phospholipidosis in Drug Development and Regulation
Table 20.1 Selection from the Combined List of Drugs that Prolong QT and/or cause Torsades de Pointes (TDP) [54]
Table 20.2 From the USFDA database of 95 Approved New Drug Applications (NDAs) that have Drug-Induced Phospholipidosis (DIPL)
LYSOSOMES
Biology, Diseases, and Therapeutics
Edited by
FREDERICK R. MAXFIELD
JAMES M. WILLARD
SHUYAN LU
Copyright © 2016 by John Wiley & Sons, Inc. All rights reserved
Published by John Wiley & Sons, Inc., Hoboken, New Jersey
Published simultaneously in Canada
No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, scanning, or otherwise, except as permitted under Section 107 or 108 of the 1976 United States Copyright Act, without either the prior written permission of the Publisher, or authorization through payment of the appropriate per-copy fee to the Copyright Clearance Center, Inc., 222 Rosewood Drive, Danvers, MA 01923, (978) 750-8400, fax (978) 750-4470, or on the web at www.copyright.com. Requests to the Publisher for permission should be addressed to the Permissions Department, John Wiley & Sons, Inc., 111 River Street, Hoboken, NJ 07030, (201) 748-6011, fax (201) 748-6008, or online at http://www.wiley.com/go/permission.
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Library of Congress Cataloging-in-Publication Data:
Names: Maxfield, Frederick R., editor. | Willard, James M., 1955- , editor. |
Lu, Shuyan, 1971- , editor.
Title: Lysosomes : biology, diseases, and therapeutics / edited by Frederick
R. Maxfield, James M. Willard, Shuyan Lu.
Other titles: Lysosomes (Maxfield)
Description: Hoboken, New Jersey : John Wiley & Sons, Inc., [2016] | Includes
bibliographical references and index.
Identifiers: LCCN 2016006834 (print) | LCCN 2016008790 (ebook) | ISBN
9781118645154 (cloth) | ISBN 9781118978306 (pdf) | ISBN 9781118978313
(epub)
Subjects: | MESH: Lysosomes
Classification: LCC QH603.L9 (print) | LCC QH603.L9 (ebook) | NLM QU 350 |
DDC 571.6/55–dc23
LC record available at https://lccn.loc.gov/2016006834
Preface
There has been a resurgence in interest in lysosomes based on exciting new discoveries over the past decade. Lysosomal function was observed microscopically in the late 19th century, and lysosomes were purified in the 1950s by the group of Christian De Duve [1]. During the same period, accumulation of undigested material in cells was observed in pathological examination of tissues from patients with a variety of diseases [2–4]. With the biochemical and morphological characterization of lysosomes, the linkage of the accumulated material with these organelles led to significant insights into the functional importance of lysosomes.
In the second half of the 20th century, there were groundbreaking studies of the biology and biochemistry of lysosomes [5–9]. These studies were linked closely with rapid developments in understanding fundamental cellular biological processes such as secretion and endocytosis. As a result, an increasingly detailed picture emerged of the biogenesis of lysosomes and their functional role in digesting internalized cargo [10, 11]. As understanding of lysosomal function increased, mechanism-based strategies for treating lysosomal diseases emerged. These included substrate reduction therapies (e.g., for Gaucher disease) [12, 13] and enzyme replacement therapies [14].
While there continued to be advances in basic cell biology and biochemistry, as well as in new therapeutic modalities, many investigators had a sense that the exciting era of discovery in lysosome biology was ending in the early 2000s. As an example, the Gordon Conference on “Lysosomes,” which for many years was one of the premier meetings on membrane traffic, changed its name to “Lysosomes and Endocytosis” in 2004.
Several related areas of investigation have blossomed over the past decade, and these have brought lysosomes back into the forefront of basic cell biology and biochemistry. One of these areas is autophagy. This process for lysosomal digestion of cytoplasmic organelles had been known for decades, but there were few handles on how to study it. With genetic studies leading to identification of key molecular components in the formation of autophagosomes and their subsequent fusion with lysosomes, it became possible to analyze this process in detail. As a result, autophagy is now recognized as playing a key role in processes including maintenance of organelle integrity, catabolism of lipid droplets, and responses to stress [15, 16]. Additionally, autophagy is essential for the survival and proliferation of some cancer cells, making it a novel target for development of therapies [17, 18]. Furthermore, genetic and molecular biological data accentuate the broad importance of the lysosome in aging and age-related diseases, including cardiovascular and neurodegenerative diseases, which make improving lysosome function an attractive target.
One of the most exciting recent developments has been the recognition that lysosomes are key regulators of signaling processes that regulate metabolism. The elucidation of the mTOR signaling pathways has shown that hydrolytic activity in lysosomes is used by the cell to sense nutrient status [19]. Among other activities, mTOR regulates autophagy to enhance the availability of new molecular building blocks when lysosomal production of catabolites is reduced. In another related area, it was recognized a few years ago that there is a coordinated transcriptional regulation of the genes involved in lysosome biogenesis [20, 21].
Along with these basic science developments, there have been important advances in the understanding of lysosomal storage disorders and in new methods for treatment. In some cases, this is beginning to turn these devastating diseases into conditions that can be managed. At the same time, there is increasing recognition that drugs used for various purposes can interact with lysosomal processes. A dramatic example of this is the discovery of mTOR as a mechanistic target for the immunosuppressive drug rapamycin [22]. Many pharmacological drugs in widespread use can affect lysosomal function [23–26], and it is important to understand the impact of these effects.
With all of these interrelated advances in understanding of lysosome biology, it seemed worthwhile to assemble an updated and integrated book on lysosomes. There are several notable earlier books on lysosomes, and a few of them will be cited here with apologies to the authors whose contributions may have been overlooked. Eric Holtzman [27] wrote a classic monograph that is still worth reading for its historical background and insights into the role of lysosomes in biology. This was followed a few years later by a book by Brian Storrie and Robert Murphy [28]. A book by Paul Saftig [29] focused on the basic biology and function of lysosomes. There have been several excellent books on lysosomal storage disorders, including one by Fran Platt and Steven Walkley [30]. More recently, there was a book emphasizing methods for the study of lysosomes [31].
The current book is intended for a broad audience of researchers interested in multiple facets of lysosome biology. Chapters 1–7 and 12 cover fundamental roles of lysosomes in physiological processes; Chapters 8–11 discusses involvement of lysosomes in various pathological conditions; Chapters 13–20 focus on the contribution of lysosomes in various aspects of drug development, including the lysosomal pathway as a target for drug discovery, toxicity, and special pharmacokinetics attributed to lysosomal accumulation and sequestration
We thank all contributors who provided their chapters despite other pressing responsibilities. We also thank our editors for their diligent effort and David B. Iaea for the cover illustration.
We hope that the broad scope, which includes both basic science and clinical applications, can promote a productive interchange among scientists working across the spectrum of lysosomal studies and nurture drug development efforts targeting lysosome pathways. Ultimately, discovery of new drugs that could improve lysosomal function will benefit multiple therapeutics areas.
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List of Contributors
Ravi K. Amaravadi
, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA
Andrea Ballabio
, Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy; Medical Genetics, Department of Translational Medicine, Federico II University, Naples, Italy; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children Hospital, Houston, TX, USA
Elfrida R. Benjamin
, Amicus Therapeutics, Cranbury, NJ, USA
Robert E. Boyd
, Amicus Therapeutics, Cranbury, NJ, USA
Thomas Burgoyne
, Department of Cell Biology, UCL Institute of Ophthalmology, University College London, London, UK
Graciana Diez-Roux
, Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy
Maureen Dougher
, Oncology Research Unit, World Wide Research and Development, Pfizer Inc., Pearl River, NY, USA
Emily R. Eden
, Department of Cell Biology, UCL Institute of Ophthalmology, University College London, London, UK
Albert De Felice
, Division of Cardiovascular and Renal Products, Office of Drug Evaluation I, Center for Drug Evaluation and Research, United States Food and Drug Administration, Silver Spring, MD, USA
Clare E. Futter
, Department of Cell Biology, UCL Institute of Ophthalmology, University College London, London, UK
Dominik Haddad
, VIB Center for the Biology of Disease, KU Leuven, Leuven, Belgium; Laboratory of Neuronal Communication, Leuven Institute for Neurodegenerative Disease (LIND), Center for Human Genetics, KU Leuven, Leuven, Belgium; Gladstone Institutes of Neurological Disease, University of California, San Francisco, CA, USA
Abigail S. Haka
, Department of Biochemistry, Weill Cornell Medical College, New York, NY, USA
Nadia Hamid
, Department of Pharmaceutical Chemistry, The University of Kansas, Lawrence, KS, USA
Marja Jäättelä
, Cell Death and Metabolism, Danish Cancer Society Research Center, Danish Cancer Society, Copenhagen, Denmark
Bart Jessen
, Drug Safety Research and Development, Pfizer Inc., San Diego, CA, USA
Jennifer Kahler
, Oncology Research Unit, World Wide Research and Development, Pfizer Inc., Pearl River, NY, USA
Tuula Kallunki
, Cell Death and Metabolism, Danish Cancer Society Research Center, Danish Cancer Society, Copenhagen, Denmark
Richie Khanna
, Amicus Therapeutics, Cranbury, NJ, USA
Judith Klumperman
, Department of Cell Biology, University Medical Center Utrecht, Utrecht, The Netherlands
Jeffrey P. Krise
, Department of Pharmaceutical Chemistry, The University of Kansas, Lawrence, KS, USA
Philip L. Leopold
, Department of Chemistry, Chemical Biology, and Biomedical Engineering, Stevens Institute of Technology, Hoboken, NJ, USA
Shuyan Lu
