The field of reversible protein acetylation has rapidly expanded in the last 4 years, giving rise to new fundamental questions and further highlighting recalcitrant ones for this evolutionarily conserved post- translational modification. From acetyl-proteomic studies, it has become evident that lysine acetylation is widespread occurring throughout the cell on hundreds of proteins. In this competitive renewal proposal, we will address these salient questions by employing global analysis of acetylation by defining regulatory mechanisms and by investigating specific examples of functional consequences of site-specific modification. The NAD+- dependent deacetylases (sirtuins) have emerged as important regulators of major biological processes, including genome maintenance, transcription, and metabolism. However, the regulation of sirtuin activity remains poorly defined. Recently, we have discovered that Sirtuin-6 (SIRT6) is activated directly by certain fatty acids. Here, we will provide the mechanistic basis and biological consequence of this activation, as well as explore this regulatory mode among all mammalian sirtuins, particularly those that display general deacylase activity (Aim 1). The lack of direct evidence for acetyltransferes in the mitochondrial has led to the possibility that substantial protein acetylation is non-enzymatic in this organelle. In this proposal, we will determine the chemical reactivities and acetylation kinetics of native mitochondrial proteins and explore the possibility that increased acetyl-CoA flux/levels are responsible for increase acetylation without the requirement for acetyltransferases (Aim 2). We have recently mapped in multiple tissues mitochondrial acetylation sites that are regulated by mouse SIRT3. The results revealed that SIRT3 controls protein acetylation in core metabolic pathways as well as tissue specific enzymes. How these acetylations control metabolism is unknown. Here, we will determine the molecular functions of reversible acetylation on mitochondrial proteins/enzymes that serve as hubs of metabolism and mitochondrial function (Aim 3). Taken together, this proposal will define fundamental principles that drive acetylation, determine regulatory mechanisms that control deacetylase activity, and reveal the molecular basis of altered activity by site-specific acetylation.
Emerging evidence suggests that a previously-unknown form of cellular and metabolic regulation exists, namely the adding and the removal of chemical acyl groups to enzymes and proteins that control metabolism and many other cellular processes. This proposal seeks to understand how these groups are added and removed, and how these events are controlled by enzymes implicated in genome maintenance, metabolism, cell survival, and lifespan. The results have the potential to transform how we understand metabolic and age- related diseases, and to generate novel therapeutic opportunities.
|Ferrer, Christina M; Alders, Marielle; Postma, Alex V et al. (2018) An inactivating mutation in the histone deacetylase SIRT6 causes human perinatal lethality. Genes Dev 32:373-388|
|Latorre-Muro, Pedro; Baeza, Josue; Armstrong, Eric A et al. (2018) Dynamic Acetylation of Phosphoenolpyruvate Carboxykinase Toggles Enzyme Activity between Gluconeogenic and Anaplerotic Reactions. Mol Cell 71:718-732.e9|
|Dhillon, Rashpal S; Denu, John M (2017) Using comparative biology to understand how aging affects mitochondrial metabolism. Mol Cell Endocrinol 455:54-61|
|Damodaran, Shivashankar; Damaschke, Nathan; Gawdzik, Joseph et al. (2017) Dysregulation of Sirtuin 2 (SIRT2) and histone H3K18 acetylation pathways associates with adverse prostate cancer outcomes. BMC Cancer 17:874|
|Lee, Jin-Hee; Yang, Bing; Lindahl, Anastasia J et al. (2017) Identifying Dysregulated Epigenetic Enzyme Activity in Castrate-Resistant Prostate Cancer Development. ACS Chem Biol 12:2804-2814|
|Deota, Shaunak; Chattopadhyay, Tandrika; Ramachandran, Deepti et al. (2017) Identification of a Tissue-Restricted Isoform of SIRT1 Defines a Regulatory Domain that Encodes Specificity. Cell Rep 18:3069-3077|
|Sanders, Dean; Qian, Shuiming; Fieweger, Rachael et al. (2017) Histone Lysine-to-Methionine Mutations Reduce Histone Methylation and Cause Developmental Pleiotropy. Plant Physiol 173:2243-2252|
|Yu, Wei; Denu, Ryan A; Krautkramer, Kimberly A et al. (2016) Loss of SIRT3 Provides Growth Advantage for B Cell Malignancies. J Biol Chem 291:3268-79|
|Hullinger, Rikki; Li, Mi; Wang, Jingxin et al. (2016) Increased expression of AT-1/SLC33A1 causes an autistic-like phenotype in mice by affecting dendritic branching and spine formation. J Exp Med 213:1267-84|
|Gregg, Trillian; Poudel, Chetan; Schmidt, Brian A et al. (2016) Pancreatic ?-Cells From Mice Offset Age-Associated Mitochondrial Deficiency With Reduced KATP Channel Activity. Diabetes 65:2700-10|
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