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Ubiquitin-Proteasome System Modulates UBIQUITIN-PROTEASOME SYSTEM MODULATES PLATELET FUNCTION NILAKSH GUPTA Bachelor in Human Genetics (Honours) Guru Nanak Dev University, Amritsar April, 2000 Master in Human Genetics (Honours) Guru Nanak Dev University, Amritsar April, 2002 Submitted in partial fulfillment of requirements for the degree DOCTOR OF PHILOSOPHY IN REGULATORY BIOLOGY at the CLEVELAND STATE UNIVERSITY June, 2014 This dissertation has been approved for the Department of Biological, Geological, and Environmental Sciences And CLEVELAND STATE UNIVERSITY College of Graduate Studies by _______________________________________________Date:____________ Dr. Thomas M. McIntyre Lerner Research Institute, Cleveland Clinic Major Advisor _______________________________________________Date:____________ Dr. Crystal M. Weyman, BGES, Cleveland State University Advisory Committee Member _______________________________________________Date:____________ Dr. Thomas Egelhoff Lerner Research Institute, Cleveland Clinic Advisory Committee Member _______________________________________________Date:____________ Dr. Jun Qin, Lerner Research Institute, Cleveland Clinic Advisory Committee Member _______________________________________________Date:____________ Dr. Barsanjit Mazumder, BGES, Cleveland State University Internal Examiner _______________________________________________Date:____________ Dr. Saurav Misra Lerner Research Institute, Cleveland Clinic, External Examiner DEDICATION This thesis is dedicated to My father Subash Gupta, My mother Rita Gupta, My mother-in-law Meenu Sharma, My wife Arishya Sharma, and My son Aryan Gupta. A very special thanks to all of you for your constant love, support, encouragement and belief in me. iii ACKNOWLEDGMENTS First I would like to thank my mentor Dr. McIntyre. He has been a great mentor in every aspect. I am truly grateful for his guidance in all aspects of my graduate studies and his willingness to always help me and discuss things whenever it was needed. He has encouraged me to always identify and pursue important questions and has demonstrated to me how to tackle scientific questions in a systematic way. His love for teaching and passion for science have been an inspiration to me I would like to thank my committee members— Dr. Crystal Weyman, Dr. Thomas Egelhoff and Dr. Jun Qin. Their feedback during my studies and for their time in reviewing my progress during my Ph.D. years is greatly appreciated. I would also like to thank my academic teachers at CSU— Dr. Mazumder, Dr. Weyman, Dr. Komar, Dr. Shukla, Dr. Li and Dr. Börner and I want to extend my gratitude to the administrative personnel at CSU, especially Monica and Carolee Pichler, for being so helpful. I would like to thank all the current and past members of McIntyre lab. They were crucial for their technical assistance, guidance and support during my training. Specifically, I would like to thank Latch and Rui for teaching me the techniques needed for the completion of this project. I would like to thank Sowmya and Padmini for assistance with experiments and moral support. I would also like to thank Dr. Wei Li for the in vivo mouse experiments. iv I would also like to thank my friends, Navneet, Manav, Arvind, Raminder, Abhishek, Shreyas, Prateek, Rashim and Vikram. I would just like to thank you guys for keeping my feet on the ground, being supportive, the nights out, holidays and general good times. Finally, I would like to thank my family. I would like to thank my mother and father for giving me the best chance possible to reach my goals throughout my childhood and into adulthood. I would like to thank my mother-in-law for her blessings and constant support. Last, but by no means least, I would like to thank my wife and son. To Arishya, for supporting me throughout this whole process and giving me the drive to keep going when things got tough. To Aryan, for being a source of inspiration and love and for being my bundle of joy. I love you guys... v ABSTRACT OF THE DISSERTATION Ubiquitin-proteasome system modulates platelet function By Nilaksh Gupta Atherothrombotic diseases are responsible for more than 25% of all deaths worldwide. Anti-platelet drugs are the mainstay treatment because of the direct involvement of platelets in the initiation and propagation of thrombosis. However, the currently available anti-platelet drugs, such as antagonists of platelet receptors or of effector systems participating in platelet activation, have their own limitations. A new mode of affecting platelet reactivity may prove to offer unique advantages in a host of clinical settings. Proteasome inhibitors are in clinical use to treat hematologic cancers, but also reduce thrombosis. Whether the proteasome participates in platelet activation or function is opaque since little is known of the proteasome in these terminally differentiated cells. Therefore, I investigated the role of proteasome- mediated proteolysis on platelet function (AIM 1). I find platelets displayed all vi three primary proteasome protease activities, which MG132 and bortezomib (Velcade®) inhibited. Proteasome substrates are marked by ubiquitin, and platelets contained a functional ubiquitination system that modified the proteome by mono- and poly-ubiquitination. Proteasome inhibition suppressed platelet aggregation by low thrombin concentrations and ristocetin-stimulated agglutination through the GPIb-IX-V complex. Proteasome inhibitor MG132 reduced stimulated spreading and clot retraction. The effects of proteasome inhibitors were not confined to a single receptor as MG132 and bortezomib suppressed thrombin-, ADP-, and LPS-stimulated microparticle shedding. Systemic MG132 strongly suppressed formation of occlusive, platelet-rich thrombi in FeCl3-damaged carotid arteries. Transfusion of platelets treated ex vivo with MG132 and washed prior to transfusion into thrombocytopenic mice also reduced carotid artery thrombosis. The inhibition of the proteasome quells the ultimate step of ubiquitin- mediated protein degradation pathway. Proteasome-mediated degradation is the final common step, however, multiple layers of regulated processes are involved upstream of this degradative machine that determines whether to target a protein for degradation or not. Platelets express a number of deubiquitinases that reverse protein ubiquitination, but their potential function in platelets is unstudied. So, I investigated the role of deubiquitinase enzymes in modulating platelet reactivity (Aim 2). I show platelets express deubiquitinase activity and specific inhibitor of the proteasome-associated deubiquitinases (b-AP15) as well as general deubiquitinase inhibitors (PYR41 and PR619) increased mono- and poly- vii ubiquitination of platelet proteins. Deubiquitinase inhibition strongly suppressed αIIbβ3 activation, degranulation, platelet aggregation and adhesion/ spreading in response to diverse platelet agonists. This inhibition also blocked downstream signaling from platelet receptors by inhibiting agonist-induced Akt phosphorylation and intracellular calcium release. Inhibition of platelet deubiquitinase activity strongly suppressed formation of platelet-rich occlusive thrombi in FeCl3-damaged murine carotid arteries and prevented in vitro thrombus formation on collagen-coated surfaces at high shear rates. Overall, this study uncovers the role of ubiquitin-proteasome system in regulating platelet reactivity and thrombosis. viii Contents ABSTRACT OF THE DISSERTATION .................................................................................................. vi CHAPTER I ........................................................................................................................................ 1 Introduction ..................................................................................................................................... 1 1.1 Overview of platelet functions and roles ............................................................................... 1 1.1.1 Role of platelets in hemostasis and thrombosis ............................................................. 3 1.1.1.1 Blood coagulation and thrombin generation........................................................... 8 1.1.1.2 Spatial and temporal heterogeneity within growing thrombus in vivo- a revised model of thrombus development ........................................................................................ 8 1.1.2 Platelet morphology and ultrastructure ....................................................................... 10 1.1.2.1 Plasma membrane (PM) and open canalicular system (OCS) ................................ 10 1.1.2.1.1 Platelet derived microparticles (PMPs) .......................................................... 12 1.1.2.2 Dense Tubular System (DTS) .................................................................................. 14 1.1.2.3 Platelet Cytoskeleton ............................................................................................. 14 1.1.2.4 Platelet Secretary Granules ................................................................................... 18 1.1.3 Platelet Receptors ......................................................................................................... 19 1.1.3.1 Adhesive receptors ................................................................................................ 19 1.1.3.1.1 Integrins .......................................................................................................... 19 1.1.3.1.2 Glycoprotein Ib-IX-V .......................................................................................
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