Characterizing the Role of NuA4 in Glucose Deprivation Stress Granule Assembly and Acetyl-CoA Signaling in Yeast

Title: Characterizing the Role of NuA4 in Glucose Deprivation Stress Granule Assembly and Acetyl-CoA Signaling in Yeast
Authors: Rollins, Meaghen
Date: 2015
Embargo: 2020-09-30
Abstract: A conserved mechanism of the cellular stress response is the formation of stress granules (SGs), cytoplasmic ribonucleoprotein (RNP) granules that contain translationally repressed messenger RNA (mRNA), translation initiation factors and numerous other proteins. Despite the strengthening association between SG assembly and cellular survival, the mechanisms regulating SG formation remain uncharacterized. Our lab identified a physical interaction between the lysine acetyltransferase (KAT) NuA4 and SG complex proteins (Pab1, Lsm12, Pbp1, and Pbp4) in Saccharomyces cerevisiae; which led us to hypothesize that lysine acetylation contributes to SG dynamics. Pab1 is a substrate for NuA4 in-vitro and the in-vivo acetylation state of Pab1 is dependent on NuA4. Further, we have determined that SG assembly upon glucose deprivation (GD) is dependent on NuA4. Thus, the objective of this project is to better define the role of NuA4 and other KATs and lysine deacetylases (KDACs) in GD SG dynamics. In addition to NuA4, the KAT Gcn5 and KDAC Rpd3 were implicated in the regulation of GD SG dynamics. It was also determined that cellular acetyl-CoA, a co-factor necessary for KAT activity, may serve as a regulator of GD SG assembly. Increasing levels of acetyl-CoA by either genetic or chemical means suppresses GD SG formation. Further, in order to identify downstream protein targets of NuA4 that may impact GD SG formation, a NuA4-dependent Pab1 protein interaction network was established under GD and non-stressed conditions. This interactome demonstrates that NuA4 impacts Acetyl-CoA Carboxylase 1 (Acc1). As Acc1 influences acetyl-CoA levels within the cell, and as acetyl-CoA impacts SG formation, this work has potentially uncovered a mechanism by which NuA4 regulates GD SG dynamics. Together this work reveals that acetyl-CoA, a metabolic readout of glucose availability, along with KAT/KDACs is a signalling pathway regulating GD SG dynamics.
CollectionThèses - Embargo // Theses - Embargo