Doctor of Philosophy, The Ohio State University, 2010, Molecular, Cellular and Developmental Biology

Autophagy is an evolutionarily conserved, degradative pathway that has been implicated in a number of physiological processes such as development and aging as well as cancer and innate immunity. This pathway is important for cell survival in starvation and is considered as a potential target for therapeutic intervention in a number of pathological conditions. Therefore, it is important that we develop a thorough understanding of the mechanisms regulating this trafficking pathway. Autophagy was initially identified as a cellular response to nutrient deprivation and is essential for cell survival during periods of starvation. During autophagy, an isolation membrane emanates from a nucleation site that is known as the phagophore assembly site (PAS). This membrane encapsulates nearby cytoplasm to form an autophagosome that is ultimately targeted to the vacuole/lysosome for degradation. The small molecules produced are then recycled and used by cells during this period of starvation. Autophagy activity is highly regulated and multiple signaling pathways are known to target a complex of proteins that contains the Atg1 protein kinase. Atg1 protein kinase activity is essential for normal autophagy in all eukaryotes and appears to be controlled tightly by a number of kinases, which target this enzyme and its associated protein partners. Our data and that of others have established that Atg1 activity is regulated, at least in part, by protein phosphorylation. In this work, we identified a particular phosphorylation event on Atg1 as an important control point within the autophagy pathway in Saccharomyces cerevisiae. This phosphorylation occurs at a threonine residue, T226, within the Atg1 activation loop that is conserved in all Atg1 orthologs. This activation loop phosphorylation is essential for Atg1 kinase activity and the induction of autophagy. The data also suggested that promoting this autophosphorylation is a primary role for two key conserved regulators of Atg1 activi (open full item for complete abstract)

Committee: Paul Herman (Advisor); Stephen A Osmani (Other); Amanda A Simcox (Other); Mark R Parthun (Other) Subjects: Cellular Biology; Genetics; Molecular Biology