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Vacuolar Proteases of Saccharomyces Cerevisiae: Characterization of an Overlooked Homolog Leads to New Functional Insights

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Vacuolar Proteases of Saccharomyces Cerevisiae: Characterization of an Overlooked Homolog Leads to New Functional Insights Vacuolar Proteases of Saccharomyces cerevisiae: Characterization of an Overlooked Homolog Leads to New Functional Insights by Katherine Rose Parzych A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy (Molecular, Cellular, and Developmental Biology) in the University of Michigan 2017 Doctoral Committee: Professor Daniel J. Klionsky, Chair Professor Matthew R. Chapman Professor Anuj Kumar Professor Lois S. Weisman Katherine Rose Parzych [email protected] ORCID iD: 0000-0002-6263-0396 © Katherine Rose Parzych 2017 Dedication To my family, with love. ii Acknowledgements Thank you to the many mentors I have had along the way. Matt Chapman, who gave me my first laboratory technician job and started me on my path towards research. Tom Bernhardt and the whole Bernhardt lab at Harvard, where my graduate career began; I am forever grateful for the solid foundation you gave me as a scientist and the camaraderie and support that made working there a joy. Thank you to my thesis committee, Matt Chapman, Anuj Kumar, and Lois Weisman, for your guidance, support, and encouragement. Thank you to the members of the Klionsky lab, past and present. You have been wonderful colleagues and fabulous friends, and you’re all wickedly smart and talented. Special thanks to Molly Day, who became one of my closest friends. Thank you to my graduate mentor, Dan Klionsky. You have been such a supportive mentor throughout this long journey. When the Rim11 project collapsed and I struggled to find my next steps, you helped me to establish a new project and discover the beauty of vacuolar proteases so that I could achieve my goals of finishing strong and showing who I really am as a scientist. You also allowed and encouraged me to pursue outside opportunities to develop my skills in science communication and teaching, which in turn helped me to be a better scientist. Thank you for sharing your humor, wisdom, and a few good books. Thank you to my friends and my incredible family, you have been my rock and my heart through all of this. Joe, you’re an amazing brother and friend. Thank you for always cheering me on and having my back. Mom and Dad, you have always encouraged me to pursue my passions, iii wherever they may lie. You have taught me to be strong, fearless, and persistent, and have been there for me when I stumbled. Graduate school has been a long road with so many challenges, and you have been there with me every step of the way. This is the hardest thing I have ever done, and I could never have gotten here without your boundless love and support. I love you. iv Table of Contents Dedication ...................................................................................................................................... ii Acknowledgements ......................................................................................................................iii List of Figures.............................................................................................................................. vii List of Tables ..............................................................................................................................viii Abstract......................................................................................................................................... ix Chapter I: Vacuolar hydrolysis and efflux: Current knowledge and unanswered questions1 Introduction .......................................................................................................................................... 1 Nucleic Acids ....................................................................................................................................... 3 Lipids.................................................................................................................................................... 4 Polyphosphate ...................................................................................................................................... 6 Carbohydrates....................................................................................................................................... 9 Organelles........................................................................................................................................... 12 Proteins............................................................................................................................................... 15 Vacuolar proteins of unknown function............................................................................................. 27 Conclusions and goals for this dissertation ........................................................................................ 28 References .......................................................................................................................................... 29 Chapter II: An overview of autophagy: Morphology, mechanism and regulation .............. 41 Abstract .............................................................................................................................................. 41 Introduction ........................................................................................................................................ 41 I. Microautophagy .............................................................................................................................. 43 v II. Chaperone-mediated autophagy (CMA)........................................................................................ 43 III. Macroautophagy........................................................................................................................... 45 Conclusions ........................................................................................................................................ 57 References .......................................................................................................................................... 67 Chapter III: A newly characterized vacuolar serine carboxypeptidase, Atg42/Ybr139w, is required for normal vacuole function and the terminal steps of autophagy in the yeast Saccharomyces cerevisiae............................................................................................................ 77 Abstract .............................................................................................................................................. 77 Introduction ........................................................................................................................................ 78 Results ................................................................................................................................................ 80 Discussion .......................................................................................................................................... 87 Materials and Methods ....................................................................................................................... 89 References ........................................................................................................................................ 101 Chapter IV: Conclusions and Future Directions ................................................................... 105 Comparative studies of Atg42/Ybr139w and Prc1........................................................................... 105 Zymogen activation cascade ............................................................................................................ 108 Lysis of autophagic bodies and effects on substrate degradation .................................................... 109 Characterization of additional proteases .......................................................................................... 110 Final Perspectives............................................................................................................................. 111 References ........................................................................................................................................ 112 vi List of Figures Figure II.1. Three types of autophagy in mammalian cells. ......................................................... 59 Figure II.2. Morphology of macroautophagy. .............................................................................. 60 Figure II.3. The induction complex consists of ULK1/2, ATG13, RB1CC1, and C12orf44....... 61 Figure II.4. The activity of the class III PtdIns3K complex is regulated by subunit composition. ....................................................................................................................................................... 62 Figure II.5. ATG12–ATG5-ATG16L1 conjugation complex. ..................................................... 63 Figure II.6. The LC3 conjugation system. .................................................................................... 64 Figure II.7. Regulation of macroautophagy.................................................................................. 65 Figure II.8. Two mechanisms of mitophagy................................................................................. 66 Figure III.1. Ybr139w is a soluble vacuolar glycoprotein............................................................ 92 Figure III.2. Vacuolar function is impaired in cells lacking PRC1 and YBR139W. ..................... 93 Figure III.3. Ybr139w
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