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Ubiquitin-Dependent Control of Myogenic Development: Mechanistic Insights Into Getting Huge, and Staying Huge

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Ubiquitin-Dependent Control of Myogenic Development: Mechanistic Insights into Getting Huge, and Staying Huge By Fernando Rodríguez Pérez A dissertation submitted in partial satisfaction of the requirements for the degree of Doctor of Philosophy in Molecular and Cell Biology in the GRADUATE DIVISION of the UNIVERSITY OF CALIFORNIA, BERKELEY Committee in charge: Professor Michael Rape, Chair Professor Roberto Zoncu Professor Jeffery Cox Professor Daniel Nomura Summer 2020 ABSTRACT Ubiquitin-Dependent Control of Myogenic Development: Mechanistic Insights into Getting Huge, and Staying Huge by Fernando Rodriguez Perez Doctor in Philosophy in Molecular and Cell Biology University of California, Berkeley Professor Michael Rape, Chair Metazoan development is dependent on the robust spatiotemporal execution of stem cell cell-fate determination programs. Although changes in transcriptional and translational landscapes have been well characterized throughout many differentiation paradigms, their regulatory mechanisms remain poorly understood. Ubiquitin has recently been found to be a key modulator of developmental programs. Ubiquitylation of target proteins occurs through a cascade of enzymatic reactions beginning with a ubiquitin activating enzyme (E1) which transfer the ubiquitin moiety to a ubiquitin conjugating enzyme (E2). The reaction is finalized by the transfer of ubiquitin to its target protein by a ubiquitin ligase (E3). Post-translational modification of proteins can lead to several different outcomes, depending on the context of the modification, known as the ubiquitin code. The precise spatiotemporal execution of ubiquitylation is critical for organismal development and homeostasis. Due to the modular and reversible nature of ubiquitylation, it is an ideal moiety in the control of a plethora of cellular processes. Cell-cell fusion is a frequent and essential event during development, whose dysregulation causes diseases ranging from infertility to muscle weakness. Critical to this process, cells repeatedly need to remodel their plasma membrane through orchestrated formation and disassembly of cortical actin filaments. In Chapter 2, I describe the identification of a ubiquitin-dependent toggle switch that establishes reversible actin bundling during mammalian cell fusion. My work identified KCTD10 as a modulator of the EPS8-IRSp53 complex, which stabilizes cortical actin bundles at sites of cell contact to push fusing cells towards each other. This work highlights how cytoskeletal rearrangements during development are precisely controlled, raising the possibility of modulating the efficiency of cell fusion for therapeutic benefit. Organismal development must rely on the timely and robust execution of quality control responses. However, how these responses modulate metazoan development is poorly understood. Showcasing the versatility of ubiquitin signaling, Chapters 3 and 4 provide insight into the role of ubiquitin in controlling stress and quality control responses. Chapter 3 describes the reductive stress response, in which FEM1B senses and reacts to persistent depletion of reactive oxygen species. Loss of ROS is detrimental for development, as it inhibits myogenesis. Concomitant to this stress response is the identification of multimerization quality control, regulated by BTBD9. MQC surveys multimeric BTB complex composition, ensuring that multimeric complexes contain the correct stoichiometries and compositions. MQC is critical for development, as loss of MQC als prevents myogenesis. These two chapters showcase the integration of ubiquitin signaling, stress/quality control pathways, and development. These writings provide a more holistic understanding into the robust regulatory underpinnings of organismal formation 1 DEDICATION Esta tesis y este trabajo, esfuerzo, sangre y sudor, se lo dedico a mi mamá Guadalupe (Jefa) y mi papá Fernando (Jefe). Gracias por todo lo que sacrificaron por mí, y por todo el apoyo que me han dado durante toda mi vida. Y claro, ¡gracias por todas las conchas y paquetitos que me mandaron y me mantuvieron vivo! Los amo. Gracias a mis hermanos, Ismael y David (Che Push y Che Bebou). Todas esas noches que nos desvelamos jugando Time Splitters, o viento Tropa de Elite, nunca pensé que nos llamaríamos doctores. No importa lo que la vida nos echó, siempre le seguimos adelante. Los amo mas o menos I guess. I want to dedicate this work to all immigrants (documented and undocumented) that have come before me, and those that will come after me. i ACKNOWLEDGEMENTS This work would not have been possible without the help of countless of people. Mentorship has been paramount for my growth as a scientist, and my work during grad school. I could not have asked for a better mentor than Michael Rape, who provided unmeasurable guidance and advice during my years here in Berkeley. You made me the scientist I am today. I’m sorry your soccer team couldn’t beat my soccer team. I am also forever thankful to the members of my thesis committee: Roberto Zoncu, Jeffery Cox, and Daniel Nomura. Your extensive guidance throughout my journey allowed me to get to where I am today. Speakin of mentors, I have to give a massive thanks to Jennifer Shepherd and Marianne Poxleitner from Gonzaga University (GO ZAGS!). You two saw my true potential and pushed me to places I did not think I could reach. Thank you. I would also like to thank all the members of the Rape lab. Especially Andrew Manford. When I sarted as a young graduate student, you dind’t hesitate to mentor me and provide some of the most critical guidance I received during my tenure as a graduate student. I will never forget our great scientific discourses, and our random talks about Mads Mikkelsen, Nicholas Cage, deep 80s synth music, Premiere League/Sports, and other countless randomness. You’re a fantastic scientist, and I hope I can get to your level sometime. I’m very honored to be able to call you my friend. Regina Baur, your countless “jokes” will not be forgotten. You made time in the lab hilarious, bearable, and overall amazing. Thanks for the bike rides! Kuan-Chuan (Eric) Pao, dude I miss you! I know you were only here briefly, but you lifted me through some of my most difficult times in the lab, and for that I will be forever thankful. I miss our basketball talks and talks about just life in general. Angela Pogson, my first undergraduate and an exemplary one at that. Besides being an amazing scientsits, you are also one of the most upbeat and optimistic people I’ve met! I still tell people about how you shred the gnar gnar. Brenda Martinez Gonzalez…que hubiera hecho sin ti!!! Thanks for always all of your help, you were there for so much, and could not have done this without you. UC Berkeley MCB is a premier research program worldwide, but the reason I decided to come here was because of the people and the sense of community. I am fortunate of being part of the MCB Class of 2014 cohort (AKA as Dankest and Tighters cohort in the history of MCB). I especiall want to thank George Otto and Rose Hill, my first roommates in Berkeley. Like the One Ring, our friendship was forged in the Fires of Casa Bonita, making it as everlasting ast he One Ring itself. George Otto, you’re a true homie, you saw me at my lowest and my highests. I could not have survived grad school without you. Could not have asked for a better friend. Robert Nichols, you brought so much laughter and joy to our whole cohort. Your energy is firkin contagious bro, thanks for Squanching with me and being a true friend. No doubt I will be seeing much more of you in the future. Don’t think I fogto about you Jesse Garcia Castillo and Santio Yori Restrepo. Ya’ll are the true homebois. All of things we went through together, and are still going through, I will never forget. I am so greatful you guys decided to come to Berkeley. Ya’ll are mi familia here. A huge thanks to the HHMI Gilliam Fam. You guys made me realize my true potential and made me feel welcome in an environement where is hard to do just that. These are trying times, as this thesis was written during a global pandemic (SARS-CoV-2), and there is no way I could have survived the last months of my PhD without some amazing groups of people. A special shoutout to the COVFee Slack Channel. Everything about you guys is hella special, and just showcases the thight-knit community of MCB here at Berkeley. The CoD Boiz and Bike Crew, so much yeetness happened with these crews. Thanks for making this quarantine livebale, and actually fun. Special shoutouts to Justin Zhang, Oscar Whitney, and Hannah Nilsson. There are many more people that have made my PhD and tenure as a graduate student possible. To all of you, thank you from the bottom of my heart. Finally, one last shout out to “Australia” by The Shins. This song got me through my darkest times, and is the most played song on my playlist, so there is that. And without further ado, here’s “Wonderwall”. ii TABLE OF CONTENTS ABSTRACT .................................................................................................................................................. 1 DEDICATION ............................................................................................................................................... i ACKNOWLEDGEMENTS ........................................................................................................................... ii TABLE OF CONTENTS ............................................................................................................................
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