通过定位微调乙酰辅酶a羧化酶1的活性:功能基因组学揭示赖氨酸乙酰转移酶NuA4和鞘脂代谢在调节Acc1活性和定位中的作用

IF 3.3 3区 生物学 Genetics Pub Date : 2022-05-24 DOI:10.1093/genetics/iyac086
T. Pham, Elizabeth A. Walden, Sylvain Huard, J. Pezacki, M. D. Fullerton, K. Baetz
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引用次数: 6

摘要

摘要乙酰辅酶A羧化酶1催化乙酰辅酶A转化为丙二酰辅酶A,这是从头合成脂肪酸的关键步骤。乙酰辅酶a羧化酶1作为脂质合成的主要调节因子,已被认为是许多代谢性疾病的治疗靶点。我们已经表明,在酿酒酵母中不存在赖氨酸乙酰转移酶NuA4的情况下,乙酰辅酶A羧化酶1的活性降低。乙酰辅酶a羧化酶1活性的这种变化与定位的变化相关。在野生型细胞中,乙酰辅酶A羧化酶1在整个细胞质中定位在小的点状和杆状结构中。然而,在NuA4突变体中,乙酰辅酶A羧化酶1的定位变得分散。为了揭示调节乙酰辅酶a羧化酶1定位的机制,我们进行了显微镜筛选,以确定影响乙酰辅酶a羧基化酶1位置的其他缺失突变体,然后通过化学遗传学和生物化学测定来测量这些突变体中乙酰辅酶a碳化酶1的活性。鉴定出三种表型。具有高活性乙酰辅酶A羧化酶1的突变体在细胞质中央形成1或2个杆状结构,具有中低乙酰辅酶A羧基化酶1活性的突变体表现出弥漫性乙酰辅酶A羧酸化酶1,而具有最低乙酰辅酶A羰基化酶1活性的突变体(低形态)在细胞外围形成厚杆状乙酰辅酶A羧化酶1结构。所有乙酰辅酶A羧化酶1亚形态突变体都与鞘脂代谢或超长链脂肪酸延伸有关,通常,它们的缺失会导致棕榈酰辅酶A的积累。通过外源性脂质处理、酶抑制剂和遗传学,我们确定增加棕榈酰辅酶A水平会抑制乙酰辅酶A羧化酶1的活性,并重塑乙酰辅酶A羧基酶1的定位。这项研究表明,酵母细胞已经形成了一种动态反馈机制,乙酰辅酶a羧化酶1的下游产物可以微调脂肪酸的合成速率。
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Fine-tuning acetyl-CoA carboxylase 1 activity through localization: functional genomics reveals a role for the lysine acetyltransferase NuA4 and sphingolipid metabolism in regulating Acc1 activity and localization
Abstract Acetyl-CoA Carboxylase 1 catalyzes the conversion of acetyl-CoA to malonyl-CoA, the committed step of de novo fatty acid synthesis. As a master regulator of lipid synthesis, acetyl-CoA carboxylase 1 has been proposed to be a therapeutic target for numerous metabolic diseases. We have shown that acetyl-CoA carboxylase 1 activity is reduced in the absence of the lysine acetyltransferase NuA4 in Saccharomyces cerevisiae. This change in acetyl-CoA carboxylase 1 activity is correlated with a change in localization. In wild-type cells, acetyl-CoA carboxylase 1 is localized throughout the cytoplasm in small punctate and rod-like structures. However, in NuA4 mutants, acetyl-CoA carboxylase 1 localization becomes diffuse. To uncover mechanisms regulating acetyl-CoA carboxylase 1 localization, we performed a microscopy screen to identify other deletion mutants that impact acetyl-CoA carboxylase 1 localization and then measured acetyl-CoA carboxylase 1 activity in these mutants through chemical genetics and biochemical assays. Three phenotypes were identified. Mutants with hyper-active acetyl-CoA carboxylase 1 form 1 or 2 rod-like structures centrally within the cytoplasm, mutants with mid-low acetyl-CoA carboxylase 1 activity displayed diffuse acetyl-CoA carboxylase 1, while the mutants with the lowest acetyl-CoA carboxylase 1 activity (hypomorphs) formed thick rod-like acetyl-CoA carboxylase 1 structures at the periphery of the cell. All the acetyl-CoA carboxylase 1 hypomorphic mutants were implicated in sphingolipid metabolism or very long-chain fatty acid elongation and in common, their deletion causes an accumulation of palmitoyl-CoA. Through exogenous lipid treatments, enzyme inhibitors, and genetics, we determined that increasing palmitoyl-CoA levels inhibits acetyl-CoA carboxylase 1 activity and remodels acetyl-CoA carboxylase 1 localization. Together this study suggests yeast cells have developed a dynamic feed-back mechanism in which downstream products of acetyl-CoA carboxylase 1 can fine-tune the rate of fatty acid synthesis.
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来源期刊
Genetics
Genetics 生物-遗传学
CiteScore
6.20
自引率
6.10%
发文量
177
期刊介绍: GENETICS is published by the Genetics Society of America, a scholarly society that seeks to deepen our understanding of the living world by advancing our understanding of genetics. Since 1916, GENETICS has published high-quality, original research presenting novel findings bearing on genetics and genomics. The journal publishes empirical studies of organisms ranging from microbes to humans, as well as theoretical work. While it has an illustrious history, GENETICS has changed along with the communities it serves: it is not your mentor''s journal. The editors make decisions quickly – in around 30 days – without sacrificing the excellence and scholarship for which the journal has long been known. GENETICS is a peer reviewed, peer-edited journal, with an international reach and increasing visibility and impact. All editorial decisions are made through collaboration of at least two editors who are practicing scientists. GENETICS is constantly innovating: expanded types of content include Reviews, Commentary (current issues of interest to geneticists), Perspectives (historical), Primers (to introduce primary literature into the classroom), Toolbox Reviews, plus YeastBook, FlyBook, and WormBook (coming spring 2016). For particularly time-sensitive results, we publish Communications. As part of our mission to serve our communities, we''ve published thematic collections, including Genomic Selection, Multiparental Populations, Mouse Collaborative Cross, and the Genetics of Sex.
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