The interplay between acetylation and lipid metabolism in Drosophila melanogaster larval development

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Miao, Ting
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Bai, Hua
Essner, Jeffrey J
Walley, Justin
Yandeau-Nelson, Marna
Yin, Yanhai
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Genetics, Development and Cell Biology
Maintaining energy homeostasis in response to altered nutrient conditions is essential for animals to sustain life and developmental growth. Like mammals, the fruit fly Drosophila melanogaster regulates its metabolism and growth in response to environmental or nutritional cues. Acetylation is a reversible post-translational modification that has emerged as one of the major players in metabolic regulation since almost all metabolic enzymes are acetylated. However, the functional roles of enzyme protein acetylation are rarely characterized, and it is largely unknown how acetylation mediates energy homeostasis during animal development. Insect development is primarily controlled by various developmental hormones, such as juvenile hormone (JH). Krüppel homolog 1 (Kr-h1), a transcription factor downstream of JH signaling, regulates key processes of insect development. Interestingly, we found that Kr-h1 controls global protein acetylation in Drosophila larval development. mRNA expression of most acetyltransferases (KATs) and deacetylases (KDACs) were dysregulated in the loss-of-function mutants Kr-h1[7]. Moreover, transcription of genes in lipogenic pathways, such as fatty acid synthase (FASN1), was significantly downregulated in Kr-h1[7]. Intriguingly, FASN1 acetylation was altered in Kr-h1[7] as well. Overall, our findings suggest that Kr-h1 may mediate the interaction between endocrine control and lipid metabolism during fly development via targeting gene transcription and protein acetylation. De novo lipogenesis (DNL) is a crucial aspect of the fruit fly developmental metabolic process. It has been well established that the functions of enzymes in the DNL pathway are regulated at transcription and translation steps. However, we unexpectedly found that protein expression of the essential lipogenic enzyme FASN1 remained at similar level from the second-instar larvae to third-instar larvae stage (L2 to L3), the stages when lipid accumulation and viii lipogenesis were highly upregulated. Instead, the acetylation level of FASN1 was significantly increased, which was correlated with its enzymatic activity. Our further genetics and biochemical studies showed that acetylation of the lysine residue K813 was required for the elevation of lipogenesis, body fat accumulation, and expected animal development timing. Protein acetylation is controlled mainly by acetyltransferases (KATs) and deacetylases (KDACs) that transfer acetyl- group from acetyl-Coenzyme A (acetyl-CoA) to the target lysine or remove acetyl- group from the lysine sites. Intriguingly, we found that K813 was nonenzymatically acetylated by acetyl-CoA in a dosage-dependent manner without the catalyzation of KATs. Furthermore, autoacetylation of K813 was mediated by a conserved P-loop-like motif (N-xx-G-x-A) nearby K813. Lastly, we found that K813 was deacetylated by Sirt1, bringing FASN activity to baseline. In summary, this work uncovers a novel role of acetyl-CoA-mediated autoacetylation of FASN1 in developmental lipogenesis and reveals a self-regulatory system that controls metabolic homeostasis by linking acetyl-CoA, lysine acetylation, and DNL. Collectively, our studies investigated the role of protein acetylation in regulating lipid metabolism during fly larval development and uncovered a novel mechanism of KATs-independent autoacetylation.