Advisory Committee Chair
David M Bedwell
Advisory Committee Members
Date of Award
Degree Name by School
Doctor of Philosophy (PhD) Heersink School of Medicine
Autophagy is the cellular mechanism of recruitment and decay of cytoplasmic molecules, proteins, and organelles that are obsolete for a particular growth condition. Autophagic degradation is distinct from proteasomal degradation by the formation of a de-novo double membrane which engulfs its cargo to be delivered for degradation to the yeast vacuole. Once thought to be only a general phenomenon of bulk decay, several autophagic pathways have demonstrated selectivity. In the following work we show that during nitrogen starvation (a potent inducer of autophagy) in the yeast Saccharomyces cerevisiae, a subset of translation factors are degraded selectively and rapidly. We go on to show that their efficient decay is dependent on a ubiquitin deubiquitinase, Ubp3p. Furthermore, we show that the proteasomal pathway is activated during nitrogen starvation and through which the selective degradation of the mRNA decay factors Dcp2p and Pop2p occurs. Interestingly, the decay of these latter factors are also dependent on Ubp3p. Ubp3p is also degraded during nitrogen starvation; we postulate as an auto-regulatory mechanism to inhibit the complete destruction of the selected proteins. Previous work in the autophagy field indicated that the mRNA of ATG8 was rapidly increased during nitrogen starvation. Since Atg8p is important for autophagosome biogenesis and expansion we sought a link between ATG8 increase and Dcp2p's decay. Our findings indicate that the 5'->3' mRNA decay pathway regulates autophagy during log growth by selectively degrading ATG8 mRNA. Furthermore, the proteasomal decay of Dcp2p coincides with an increase in ATG8 mRNA half-life during nitrogen starvation. This work has uncovered a novel mechanism of autophagic regulation that may be used to modulate autophagy to influence therapeutic outcomes.
Kelly, Shane Patrick, "Changes In Gene Expression During Nitrogen Starvation Are Mediated By Targeted Degradation Of Translation And Mrna Decay Factors In Saccharomyces Cerevisiae" (2015). All ETDs from UAB. 2121.