Ral G-Proteins and the Exocyst Complex are Mediators of the Cellular Response to Nutrients

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dc.contributor.advisorWhite, Michael A.en
dc.creatorBodemann, Brian Oliveren
dc.date.accessioned2012-07-20T18:18:45Z
dc.date.available2012-07-20T18:18:45Z
dc.date.issued2012-07-20
dc.description.abstractThe small G-proteins, RalA and RalB, are important mediators of cellular responses to viral infection and nutrient availability. Prior work has demonstrated that the exocyst complex is an important effector of Ral G-protein signaling. The eight member exocyst contains two Ral effector proteins, Exo84 and Sec5, which contribute to distinct cellular responses. During viral infection, RalB promotes the activation of the innate immunity signaling kinase, TBK1, through direct assembly on a Sec5-containing subcomplex of the exocyst. Macroautophagy is an important cellular process which facilitates cellular adaptation to nutrient deprivation as well as the clearance of intracellular pathogens. The study of macroautophagy in mammalian cells has described induction, vesicle nucleation, and membrane elongation complexes as key signaling intermediates driving autophagosome biogenesis. How these components are recruited to nascent autophagosomes is poorly understood, and although much is known about signaling mechanisms that restrain autophagy, the nature of positive inductive signals that can promote autophagy remain cryptic. I report that RalB is localized to nascent autophagosomes. RalB and its effector Exo84 are required for nutrient starvation-induced autophagocytosis, and RalB activation is sufficient to promote autophagosome formation. Through direct binding to Exo84, RalB induces the assembly of ULK1 and Beclin1-VPS34 complexes on the exocyst, which are required for isolation membrane formation and maturation. Thus, RalB-Exo84 signaling is a primary adaptive response to nutrient limitation that directly engages autophagocytosis through mobilization of the core vesicle nucleation machinery. Conversely, I find that Sec5 associates with mTORC1, a key inhibitor of autophagy. Intriguingly, I find that the Ral–Sec5 activated kinase, TBK1, is necessary for amino acid stimulation of mTORC1 activity. Thus, distinct Ral-dependent subcomplexes of the exocyst mediate the cellular response to nutrient availability.en
dc.identifier.oclc811140483
dc.identifier.urihttps://hdl.handle.net/2152.5/1015
dc.language.isoenen
dc.subjectral GTP-Binding Proteinsen
dc.subjectGene Expression Regulation, Enzymologicen
dc.subjectNeoplasmsen
dc.titleRal G-Proteins and the Exocyst Complex are Mediators of the Cellular Response to Nutrientsen
dc.typeThesisen
dc.type.materialTexten
thesis.date.available2014-01-14
thesis.degree.departmentGraduate School of Biomedical Sciencesen
thesis.degree.disciplineCell Regulationen
thesis.degree.grantorUT Southwestern Medical Centeren
thesis.degree.levelDoctoralen
thesis.degree.nameDoctor of Philosophyen

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