Lipid raft mediation of desmoglein function Open Access

Lewis, Joshua (Fall 2017)

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Desmosomes are robust cell-cell adhesion structures which enable tissues to withstand mechanical stress. Desmosomes are abundant in cardiac tissue, in the epidermis, and in various epithelial tissues which must withstand mechanical stress. Desmosomes are dense, protein-based structures which span the plasma membranes of two neighboring cells in order to anchor them together. Many of the basic mechanisms of desmosome assembly and regulation are currently unknown, although recent evidence indicates that specialized membrane microdomains, termed lipid rafts, are required for desmosome assembly. This dissertation explores the importance of lipid rafts for desmosome assembly and function.

Direct cell-cell adhesion is mediated by the desmosomal cadherins. Cadherins are transmembrane proteins which extend into the extracellular space between cells and directly bind to a cadherin from a neighboring cell. There are two families of desmosomal cadherins: desmogleins and desmocollins. The cytoplasmic domain of the cadherin is bound by desmosomal plaque proteins which serve as adaptor molecules to link the cadherin to the cell’s keratin cytoskeleton. All of the major desmosomal proteins are associated with lipid rafts, and loss of lipid raft association impairs desmosome function.

This dissertation explores a human disease caused by a mutation in a desmoglein, DSG1. The mutation causes a hydrophobic-to- hydrophilic substitution in the DSG1 transmembrane domain, abrogating the protein’s lipid raft association. The non-raft mutant is defective in its trafficking through the secretory pathway, with a significant amount of protein retained in the Golgi apparatus. Mutant DSG1 which reaches the cell surface fails to incorporate into desmosomes. This dissertation also investigates the desmoglein family more broadly, determining which features are and are not important for lipid raft targeting, and the functional consequences to loss of raft targeting. DSG3, which is targeted in the human autoimmune disease Pemphigus Vulgaris, is also investigated.

Table of Contents

1 Dissertation overview and significance

2 Introduction

2.1 Introduction to desmosomes

2.2 Molecular components of the desmosome

2.3 Regulation of the desmosome

2.4 Desmosome involvement in intracellular signaling

2.5 Diseases of the desmosome

2.6 Introduction to lipid rafts

2.7 Lipid diversity in cell membranes

2.8 Characteristics of lipid rafts

2.9 Membrane proteins and lipid rafts

2.10 Lipid raft involvement in secretory pathway trafficking

2.11 Platform for protein segregation and concentration

2.12 Lipid rafts and human disease

2.13 Introduction to lipid raft involvement in desmosome assembly, function, and disassembly

2.14 Evidence for desmosome association with lipid rafts

2.15 Lipid raft perturbation inhibits desmosome assembly, disassembly, and function

3 A mutation in the desmoglein 1 transmembrane domain abrogates lipid raft targeting and causes severe dermatitis, multiple allergies, and metabolic wasting (SAM) syndrome

3.1 Introduction

3.2 Results & Discussion

3.3 Acknowledgements

3.4 Figures

3.5 Methods and materials

4 Loss of Desmoglein Partitioning to Detergent Resistant Membranes is not Sufficient to Cause Trafficking Defect or Mislocalize an Endogenous Desmoglein

5 Dissertation summary and future directions

6 References

About this Dissertation

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