Cholesterol and PI(4,5)P2 in Vital Biological Functions: From Coexistence to Crosstalk

Description

Cholesterol is an essential component of the plasma membrane. Phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2), although a minor phospholipid, is the most abundant membrane phosphoinositide. Both lipids play key roles in a variety of cellular functions including as signalling molecules and major regulators of protein function. Studies on these important lipids have traditionally focused on the effect of each lipid individually. Accumulating evidence indicates, however, that these lipids may cross-regulate each other’s levels. Furthermore, it is becoming evident that cholesterol and PI(4,5)P2 can act together to modulate protein function and biological processes. This book provides an overview of cellular functions and molecular mechanisms in which cholesterol and PI(4,5)P2 functions extend from parallel existence to crosstalk. It includes four sections. The first section introduces the reader to cholesterol and PI(4,5)P2. The second section demonstrates the mutual influence of these two critical lipids on their levels. The third section, divided into two parts, describes the co-modulation of protein function by cholesterol and PI(4,5)P2. The first part focuses on ion channels and the second - on lipid transfer proteins. The fourth section highlights other cellular processes at the intersection of cholesterol and PI(4,5)P2 involvement. Collectively, the book portrays the emerging relationship between cholesterol and PI(4,5)P2 in a broad array of biological systems and processes. The book will be of interest to a wide audience of research scientists with an interest in the biophysical properties of lipids and the physiological consequences of their presence in biological systems, as well as graduate students, postdoctoral trainees, basic and clinical researchers, and pharmaceutical scientists. Specifically, the content will be relevant to researchers in the fields of biochemistry, molecular biophysics, pharmacology, neurobiology, cardiovascular biology, among others. Provides a comprehensive overview of the current knowledge of the interplay between cholesterol and PI(4,5) P2 Provides an overview of the emerging relationship between cholesterol and PI(4,5)P2 in biological systems and processes Discusses cellular processes and molecular mechanisms where lipid functions extend from parallel existence to crosstalk Preface Contents About the Editor Part I: Introduction to Cholesterol and PI(4,5)P2 Untitled PI(4,5)P2 and Cholesterol: Synthesis, Regulation, and Functions 1 Introduction 2 Phosphatidylinositol Phosphates (PIPs) 2.1 PIPs: Overview, Structure, Synthesis, and Membrane Distribution 2.1.1 Headgroup 2.1.2 Acyl Chains 2.1.3 Membrane Distribution 2.2 Functions of PIPs 2.2.1 PIP2-Dependent Processes 2.2.1.1 Endocytosis/Exocytosis 2.2.1.2 Intracellular Trafficking 2.2.1.3 Actin Dynamics 2.2.1.4 Focal Adhesion Dynamics 2.2.1.5 Membrane Curvature 2.2.1.6 Lipid Transfer 2.2.2 Regulation of Signaling Transmembrane Proteins 2.2.2.1 G-Protein-Coupled Receptors (GPCRs) 2.2.2.2 Ion Channels 2.2.3 Cellular Signaling 2.2.3.1 Receptor-Stimulated Phospholipases C 2.3 Methods to Monitor Membrane PIP Levels 3 Cholesterol 3.1 Cholesterol: Overview and Structure 3.2 Biosynthesis, Regulation, and Metabolism of Cholesterol 3.3 Side Products Along the Mevalonate Pathway and Downstream of Cholesterol 3.4 Functions of Cholesterol 3.4.1 Cell Membranes 3.4.2 Lipid Rafts 3.4.3 Cholesterol as a Principal Component in Myelin 3.4.4 Endocytosis and Exocytosis 3.4.5 Signaling Processes Involving Cholesterol 3.4.5.1 Proteins: Receptors and Ion Channels 3.4.5.2 Estrogen-Related Receptor α-Signaling 3.4.5.3 Hedgehog Signaling 3.5 Methods for Altering Cholesterol Levels 3.5.1 In Vitro Approaches to Alter Cholesterol Levels 3.5.2 In Vivo Approaches to Alter Cholesterol Levels 4 Outlook References Biophysics of Membrane Stiffening by Cholesterol and Phosphatidylinositol 4,5-bisphosphate (PIP2) 1 Introduction 1.1 Cholesterol and PIP2 Affect Membrane Mechanical Properties 2 Introduction to Solid-State NMR Spectroscopy 2.1 Principles of Solid-State 2H NMR Spectroscopy 2.2 Membrane Bilayer Properties by Solid-State 2H NMR Spectroscopy 2.3 Membrane Rigidity by Solid-State 2H NMR Spectroscopy 3 Introduction to Neutron Spin-Echo Spectroscopy 3.1 Principles of Neutron Spin-Echo Spectroscopy 3.2 Membrane Undulations 3.3 How Does the Membrane Thickness Fluctuate? 4 Biophysical Conclusions and Outlook References Part II: Mutual Influence of Cholesterol and PI(4,5)P2 on Their Levels Mechanism of the Regulation of Plasma Cholesterol Levels by PI(4,5)P2 1 Cholesterol Within the Circulation 1.1 VLDL and LDL Metabolism 1.2 HDL Metabolism 1.3 The Role of the Intestine in Cholesterol Metabolism 2 TMEM55B, a PI(4,5)P2 Phosphatase, Modulates Circulating Cholesterol Through Lysosomal Decay of the Low-Density Lipoprotein Receptor 2.1 Significance of LDLR 2.2 Overview of LDLR Trafficking 2.3 PI(4,5)P2 and LDLR Internalization 2.4 PI(4,5)P2 and the Lysosome 2.5 Mechanisms of LDLR Lysosomal Decay 2.6 TMEM55B and LDLR 2.6.1 In Vitro Studies of TMEM55B and LDLR 2.6.2 In Vivo Studies of TMEM55B 2.6.3 Questions Regarding the TMEM55B-PI(4,5)P2-LDLR Axis and Its Impact on LDL Cholesterol 3 PI(4,5)P2 and HDL Cholesterol 4 PI(4,5)P2 May Indirectly Impact Circulating Cholesterol Through Its Effects on Insulin Signaling 5 Regulation of PI(4,5)P2 by Cholesterol 6 Chapter Summary References Cholesterol and Phosphoinositides in Cilia Biology 1 Introduction 2 The Cilium 2.1 The Different Compartments of Cilia 2.2 Ciliary Function and Consequences of Dysfunction 2.3 Ciliary Signaling: The Hedgehog Pathway 2.4 Cholesterol-Mediated Modulation of Hedgehog Signaling 2.5 Cholesterol-Dependent Ciliopathies 2.5.1 Smith-Lemli-Opitz Syndrome (OMIM 270400) 2.5.2 Zellweger Syndrome (OMIM 214100) 2.5.3 Niemann-Pick Type C Disease (NPC) 2.6 Phenotypes Caused by Manipulation of Cholesterol Levels in Animal Models 2.7 How Cholesterol Changes Cilia? 2.8 Cilia in Cholesterol Ciliopathies 2.9 Molecular Mechanism of Cholesterol’s Impact on Ciliogenesis 3 Summary References Alterations in Cholesterol and Phosphoinositides Levels in the Intracellular Cholesterol Trafficking Disorder NPC 1 NPC Disease 2 NPC and Cholesterol 2.1 Cholesterol: Structure and Distribution 2.2 NPC Proteins: Interactions with Cholesterol and Role in Cholesterol Transport 2.3 Modulation of Cholesterol Efflux 3 NPC and Phosphoinositides: Beyond Cholesterol 3.1 Phosphoinositides: Structure and Distribution 3.2 Alterations in Phosphoinositides in NPC Disease 4 Outlook References Part III: Co-regulation of Protein Function by Cholesterol and PI(4,5)P2 Untitled From Crosstalk to Synergism: The Combined Effect of Cholesterol and PI(4,5)P2 on Inwardly Rectifying Potassium Channels 1 Introduction 2 PI(4,5)P2 and Cholesterol Binding to Kir Channels 3 Insights into the Biophysical Mechanisms of PI(4,5)P2 and Cholesterol Modulation of Kir2 and Kir3 Channels 4 Insights into the Molecular Mechanisms of PI(4,5)P2 and Cholesterol Modulation of Kir2 and Kir3 Channels 5 Crosstalk Between PI(4,5)P2 and Cholesterol in the Modulation of Kir2 Channels 6 Synergism Between PI(4,5)P2 and Cholesterol in the Modulation of Kir3.2 and Kir3.4 Channels 7 Outlook References Role of Lysosomal Cholesterol in Regulating PI(4,5)P2-Dependent Ion Channel Function 1 Introduction 2 PI(4,5)P2-Dependent Control of Ion Channel Function 2.1 Phosphoinositide Biogenesis 2.2 Plasma Membrane PI(4,5)P2 Metabolism 2.2.1 Phosphatidylinositol (PI) 2.2.2 Phosphatidylinositol 4 Phosphate (PI4P) 2.2.3 Phosphatidylinositol 4,5 Bisphosphate (PI(4,5)P2) 2.3 PI(4,5)P2-Dependent Ion Channels 2.3.1 Tools for Testing PI(4,5)P2-Dependent Ion Channel Function 2.3.2 PI(4,5)P2-Dependent Ion Channels 3 Cholesterol-Dependent Control of Ion Channel Function 3.1 Cholesterol Metabolism 3.2 Plasma Membrane Cholesterol 3.3 Cholesterol-Dependent Ion Channel Function 3.3.1 Tools for Testing Cholesterol-Dependent Ion Channel Function 3.3.2 Cholesterol-Dependent Ion Channels 4 Lysosomal Cholesterol Controls PI(4,5)P2-Dependent Ion Channel Activity 4.1 Lysosomal Cholesterol 4.2 Sterol Regulatory Element Binding Protein (SREBP) 4.3 Loss of NPC1 Function Reduces Plasma Membrane PI(4,5)P2 4.3.1 Reduced PI(4,5)P2 in NPC Disease Alters Ion Channel Activity 4.3.2 Lysosomal Control of KV7.2/3 Channel Activity Influences Excitability 4.3.3 Perspectives and Future: NPC1 Control of PI(4,5)P2-Senstiive Ion Channels 5 Conclusions References Cholesterol and PIP2 Modulation of BKCa Channels 1 Introduction 2 Regulation of BKCa Channels by PIP2 2.1 Structural Determinants for PIP2 and Related Phosphoinositides to Regulate BKCa Channel Function 2.2 PIP2 Recognition Site(s) in BKCa Channel Subunits 2.3 Tissue-Specificity and Physiological Significance of PIP2-BKCa Channel Interactions 3 Regulation of BKCa Channels by Cholesterol 3.1 Cholesterol Modulation of BKCa Channels: Lipid- vs. Protein-Driven Mechanisms 3.2 Cholesterol Modulation of Homomeric Slo1 Channels 4 Modulation of BKCa Channel Function by Cholesterol and PIP2: Is There a Possibility of Molecular Crosstalk Between Sterol and Phosphoinositide? 4.1 Cholesterol-PIP2 Interactions at the BKCa α Subunit 4.2 Cholesterol and PIP2 Modulation of BKCa Channels Beyond α Subunits 5 Concluding Remarks References Regulation of ThermoTRP Channels by PIP2 and Cholesterol 1 General Properties of TRP Channels 2 Functions, Structures, and Binding Sites in TRP Channels 3 Roles of PIP2 and Cholesterol in the Function of Different ThermoTRP Channels 3.1 TRPA1 Channels 3.2 TRPV Channels 3.3 TRPM Channels 4 Conclusions References Phosphatidylinositol 4,5-Bisphosphate and Cholesterol Regulators of the Calcium-Activated Chloride Channels TMEM16A and TMEM16B 1 Introduction 1.1 Calcium-Dependent Chloride Channels TMEM16A and TMEM16B 2 TMEM16A Requires PI(4,5)P2 for Activation 3 How Can PI(4,5)P2 Control TMEM16A Function? 3.1 The Cytosolic Side of TMEM16A Has Several PI(4,5)P2-Binding Sites 3.2 Modular Structure, Cooperative Gating, and PI(4,5)P2-Induced Pore Dilation 4 Is TMEM16B Inhibited by PI(4,5)P2? 5 Cholesterol and PI(4,5)P2: Friends and Foes in Ion Channel Regulation 6 Closing Comments References Roles of Cholesterol and PtdIns(4,5)P2 in the Regulation of STIM1–Orai1 Channel Function 1 Introduction 2 Phosphoinositides 3 Cholesterol 4 STIM and Orai 5 ER–PM Contact Sites 6 Lipids Rafts 7 STIM1 and Orai1 Regulation by Phosphoinositides 8 Cholesterol Effect on SOCE 9 Molecular Insights of Cholesterol Interactions with Orai1 and STIM1 10 Conclusion References Roles of Phosphatidylinositol 4-Phosphorylation in Non-vesicular Cholesterol Trafficking 1 A Connection Exists Between Oxysterol-Binding Proteins and Phosphoinositides 1.1 The Discovery of OSBP as an Oxysterol-Binding Protein 1.2 Phosphoinositides Determine the Localization of OSBP as Well as Its Mammalian and Yeast Orthologues 1.3 OSBP-Dependent Sterol Transport Is Driven by PI4P Gradients 1.4 Effector Functions of OSBP Family Proteins Through the Control of PI4P Levels 1.5 ORPhillins: A New Class of Drugs Targeting OSBP and Other ORPs 2 ORPs and Osh Proteins Control a Variety of Lipid Transport Processes Using PI4P Gradients 2.1 Mammalian ORPs 2.2 Yeast Osh Proteins 3 The Close Connection Between Chol Transport and the Distribution of Other Lipids Is Driven by PPIns 3.1 A New Family of Chol Transfer Proteins Is Identified 3.2 PS Distribution and Metabolism Affects Chol Transport 4 Concluding Remarks References Crosstalk Between Cholesterol, ABC Transporters, and PIP2 in Inflammation and Atherosclerosis 1 Introduction 2 Cholesterol-Lowering, the Gold Standard for CVD Problem 3 Role of Phosphatidylinositol 4,5-Bisphosphate (PIP2) in Reverse Cholesterol Transport (RCT) 4 PIP2 Is Effluxed to ApoA1 Along with Cholesterol 5 PIP2 Levels Modulate Cellular Cholesterol Efflux Capacity 6 Crosstalk Between Free Cholesterol, Autophagy, and Sphingolipids in CVD 7 Efferocytosis, Gut Microbiota, and Inflammasomes: The Emerging Anti-CVD Targets 8 Gasdermin D Activity in CVD 9 Inflammasomes: A New Frontier for CVD Therapeutics 10 Pyroptosis in Atherosclerotic Plaques 11 Summary References Part IV: Cellular Processes at the Intersection of Cholesterol and PI(4,5)P2 Involvement Role of PI(4,5)P2 and Cholesterol in Unconventional Protein Secretion 1 Introduction 2 Homeoproteins: Unexpected Intercellular Messengers 3 Homeoprotein–Lipid Interaction 4 Requirement of PI(4,5)P2 in Unconventional Secretion 5 Requirement of PI(4,5)P2 in the Translocation of EN2 Homeoprotein 6 Mechanism of Action of PI(4,5)P2 7 Role of Cholesterol in Unconventional Secretion 8 Conclusion References Ca2+ and Annexins – Emerging Players for Sensing and Transferring Cholesterol and Phosphoinositides via Membrane Contact Sites 1 Introduction 2 Cellular Ca2+ Handling and CBPs in Lipid Homeostasis 3 Proximity Matters – Crosstalk of Lipid Transfer Proteins and Ca2+ Effectors at Membrane Contact Sites 3.1 Beyond LTPs – Other Proteins That Move Cholesterol Across MCS 4 Annexins and Lipid-Binding Empathies 4.1 AnxA1 Couples Cholesterol Transfer Across MCS with Downregulation of Growth Factor Receptors 4.2 AnxA6 Regulates MCS-Mediated Cholesterol Egress from Late Endosomes 4.3 AnxA2 and AnxA8 Influence the Cellular Distribution of PI(4,5)P2 and Cholesterol 5 PI Switches, Cholesterol Transfer, Ca2+ Signalling and MCS in the Recycling Endosomal Compartment (REC) 5.1 MCS Between EE and the ER Define Sites for the Biogenesis of the REC 5.2 PI Signalling in the REC of Polarized Cells 6 PIs and MCS in Other Intracellular Trafficking Events 6.1 PIs in LE/Lys Contribute to the Regulation of Autophagy 6.2 PIs and CBPs Along Exocytic Pathways 7 Concluding Remarks References Index