Patrick Dennis (Advisor)
Doctor of Philosophy (PhD)
Healthy cells maintain a dynamic and responsive intracellular environment that is marked by the synthesis and degradation of proteins, complex macromolecules and organelles. Autophagy, literally "self-eating," is a mechanism that delivers cellular cargo to the lytic compartment for digestion. Defects in the regulation of autophagy have been implicated in pathologies such as cancer and neurodegenerative disease, making the study of its regulation compelling. However, few studies have looked at the regulation of mammalian autophagy as a function of a specific cargo protein. Previous studies had indicated that the metabolic enzyme betaine homocysteine methyltransferase (BHMT) is degraded through an autophagic mechanism. One aim of this study has centered on the role of BHMT quaternary structure in determining the efficiency of autophagic sequestration and degradation. In these studies, an oligomerization deficient form of BHMT was used to show that modulation of the Class III PI3 kinase signaling pathway is likely involved in discerning monomeric from multimeric BHMT and that this has a role in the subsequent degradation of BHMT by autophagy. The second aim has been to study to role of the nutrient-regulated mTOR pathway in the autophagic degradation of BHMT. It has been proposed that mTOR-mediated inactivation of S6 kinase is required for induction of autophagy in mammals. However in Drosophila melanogaster, S6 kinase activity has been shown to be essential for induction of autophagy. The current study demonstrates that the inhibitory signal from mTOR to autophagy does not go through S6 kinase or subsequent phosphorylation of the ribosomal protein S6. The significance of these observations in terms of misfolded proteins, neurodegenerative diseases and therapeutics is discussed.
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