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Full Dissertation Distribution Agreement In presenting this thesis or dissertation as a partial fulfillment of the requirements for an advanced degree from Emory University, I hereby grant to Emory University and its agents the non-exclusive license to archive, make accessible, and display my thesis or dissertation in whole or in part in all forms of media, now or hereafter known, including display on the world wide web. I understand that I may select some access restrictions as part of the online submission of this thesis or dissertation. I retain all ownership rights to the copyright of the thesis or dissertation. I also retain the right to use in future works (such as articles or books) all or part of this thesis or dissertation. Signature: _____________________________ _________________ Pearl Victoria Ryder Date Actin Cytoskeleton Regulators Interact with the Hermansky-Pudlak Syndrome Complex BLOC-1 and its Cargo Phosphatidylinositol-4-kinase Type II Alpha By Pearl Victoria Ryder Doctor of Philosophy Graduate Division of Biological and Biomedical Science Biochemistry, Cell and Developmental Biology ____________________________________________ Victor Faundez, M.D., Ph.D. Advisor ____________________________________________ Douglas C. Eaton, Ph.D. Committee Member ____________________________________________ Andrew P. Kowalczyk, Ph.D. Committee Member ____________________________________________ Lian Li, Ph.D. Committee Member ____________________________________________ Winfield S. Sale, Ph.D. Committee Member Accepted: ___________________________________________ Lisa A. Tedesco, Ph.D. Dean of the James T. Laney School of Graduate Studies ___________________ Date Actin Cytoskeleton Regulators Interact with the Hermansky-Pudlak Syndrome Complex BLOC-1 and its Cargo Phosphatidylinositol-4-kinase Type II Alpha By Pearl Victoria Ryder B.A., University of Chicago Advisor: Victor Faundez, M.D., Ph.D. An abstract of A dissertation submitted to the Faculty of the James T. Laney School of Graduate Studies of Emory University in partial fulfillment of the requirements for the degree of Doctor of Philosophy Graduate Division of Biological and Biomedical Sciences Biochemistry, Cell and Developmental Biology 2013 Abstract Actin Cytoskeleton Regulators Interact with the Hermansky-Pudlak Syndrome Complex BLOC-1 and its Cargo Phosphatidylinositol-4-kinase Type II Alpha By Pearl Victoria Ryder Vesicle biogenesis machinery components such as coat proteins can interact with the actin cytoskeleton for cargo sorting into multiple pathways. However, whether or not these interactions are a general requirement for the diverse endosome traffic routes is unknown. In this dissertation, I identified actin cytoskeleton regulators as previously unrecognized interactors of complexes associated with the Hermansky- Pudlak syndrome. Two complexes mutated in the Hermansky-Pudlak Syndrome, AP-3 and BLOC-1, interact with and are regulated by the lipid kinase PI4KIIα. I therefore hypothesized that PI4KIIα interacts with novel regulators of these complexes. To test this hypothesis, I immunoaffinity purified PI4KIIα from isotope- labeled cell lysates (SILAC) to quantitatively identify interactors. Strikingly, PI4KIIα isolation preferentially co-enriched proteins that regulate the actin cytoskeleton, including guanine exchange factors for Rho family GTPases such as RhoGEF1 and several subunits of the WASH complex. I biochemically confirmed several of these PI4KIIα interactions. Importantly, BLOC-1 complex, WASH complex, RhoGEF1, or PI4KIIα depletions altered the content and/or subcellular distribution of the BLOC- 1-sensitive cargoes PI4KIIα, ATP7A, and VAMP7. I conclude that the Hermansky- Pudlak syndrome complex BLOC-1 and its cargo PI4KIIα interact with regulators of the actin cytoskeleton. Exploring these interactions will provide insight into the regulation of actin polymerization at endosomes and the pathogenic mechanisms of human diseases such as pigmentation disorders, neurocutaneous syndromes, and neurodegeneration. Actin Cytoskeleton Regulators Interact with the Hermansky-Pudlak Syndrome Complex BLOC-1 and its Cargo Phosphatidylinositol-4-kinase Type II Alpha By Pearl Victoria Ryder B.A., University of Chicago Advisor: Victor Faundez, M.D., Ph.D. A dissertation submitted to the Faculty of the James T. Laney School of Graduate Studies of Emory University in partial fulfillment of the requirements for the degree of Doctor of Philosophy Graduate Division of Biological and Biomedical Sciences Biochemistry, Cell and Developmental Biology 2013 Acknowledgments I would to start by thanking my mentor and advisor, Victor Faundez. Victor has always been available with a kind and encouraging word. Throughout my PhD studies, he has taught me how to build and then tell a cellular story. Moreover, he has demonstrated a humanistic approach to success in academic science and scholarship and I feel grateful to have him as a role model. In addition to my mentor, I would like to thank the Faundez laboratory members for sharing their curiosity, enthusiasm, and feedback on my work. My thesis committee members have been instrumental to my success during this degree program and I am grateful to have had a committee where I could look forward to our meetings. I would particularly like to thank Win Sale for his advice through the years, particularly with respect to the Physiology Course at Woods Hole. I cannot imagine a better capstone to my PhD experience and am thankful for his encouragement and support during my application. Lastly, I am particularly grateful to Drs. Bill Eley and Ira Schwartz, for recognizing that my skills and personality would fit well at Emory University School of Medicine and recruiting me to attend. Of course, I must thank my family and friends for their support during this experience. My friends from high school, college, medical school, and Atlanta have enriched my life and made graduate school a joyful process. My sisters are incredible role models and as a younger sibling, I have looked to their experiences to shape and guide my own. Finally, my parents have always pushed me and encouraged me to do good work. Through their own examples as boatbuilder and craftswoman, they have shown me that attention to detail and teamwork matters and to try to do it right the first time. My mother is the original storyteller in my family and has taught me to speak and write as clearly as possible. Finally, their support and love have enabled me to leap for new experiences at University of Chicago and Emory University with the security that I can fall back on them if needed. Table of Contents Page Number Chapter I. General Introduction. 1 Overview and significance 2 Fundamental Principles of Membrane Trafficking 4 Endocytic and secretory organelles exchange components by membrane trafficking 4 Adaptor protein complexes link coat complexes with cargo at specific subcellular domains 5 Figure 1. Adaptor-mediated vesicular transport creates and maintains unique organelle composition. 8 AP-2-dependent vesicle budding at the plasma membrane 8 Figure 2. The canonical vesicle budding process: AP-2-dependent clathrin-mediated endocytosis. 10 The role of actin polymerization in AP-2-dependent vesicle budding 11 The adaptor protein complex-3 (AP-3) 13 Figure 3. Composition of the adaptor protein complex-3 (AP-3). 14 AP-3 deficiency causes the Hermansky-Pudlak syndrome 15 The biogenesis of lysosome-related organelles complex-1 (BLOC-1) 18 Figure 4. Subunit composition of the biogenesis of lysosome-related organelles complex-1 (BLOC-1). 19 Possible functions of the BLOC-1 complex 19 Possible molecular mechanisms of BLOC-1 function 20 The phosphatidylinositol 4-kinase type IIα is a cargo and a regulator of AP-3 and BLOC-1 22 Initial characterization of phosphatidylinositol kinases 23 The type II phosphatidylinositol 4-kinases 24 Figure 5. Domain architecture of phosphatidylinositol 4-kinase type IIα (PI4KIIα). 25 PI4KIIα is a component of the canonical Wnt signaling pathway 25 Figure 6. Model for regulation of PI4KIIα activity by the Wnt signaling pathway. 26 PI4KIIα is a cargo and a regulator of the BLOC-1 and AP-3 complexes 27 Figure 7. Model for regulation of the AP-3 and BLOC-1 complexes by PI4KIIα. 28 The actin cytoskeleton and its regulators 29 Actin monomers polymerize into structural units critical for cellular function 29 Regulation of actin polymerization in vivo: small GTPases and guanine exchange factors 31 Figure 8. The RhoA GTPase cycle and regulation by Rho guanine exchange factor-1 (RhoGEF1). 35 The Arp 2/3 complex nucleates and organizes actin filaments 35 Nucleation-promoting factors (NPFs) 36 Figure 9. Nucleation of actin polymerization by the Arp2/3 complex and nucleation-promoting factors. 38 The Wiskott-Aldrich Syndrome Proteins 38 The WASP and Verprolin Homolog (WAVE) Proteins 39 WASP and SCAR Homolog (WASH) 40 Localization 41 Function 42 Mechanism of action 43 Figure 10. Proposed mechanism of action for WASH-dependent membrane scission. 44 Figure 11. Potential roles for the actin cytoskeleton in endosomal sorting. 45 Regulation 46 Figure 12. The WAVE and WASH actin nucleation-promoting factors are incorporated into structurally analogous complexes. 47 Contributions of this dissertation research 49 Chapter II. The WASH Complex, an Endosomal Arp2/3 Activator, Interacts with the Hermansky-Pudlak Syndrome Complex BLOC-1 and its Cargo Phosphatidylinositol-4-kinase Type II Alpha 51 Abstract 52 Introduction 53 Results 57 The PI4KIIα interactome enriches actin regulatory proteins
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