Dynamic protein deacetylation is a limited carbon source for acetyl-CoA-dependent metabolism.
Dynamic protein deacetylation is a limited carbon source for acetyl-CoA-dependent metabolism.
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DOI：
10.1016/j.jbc.2023.104772
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发表时间：
2023-06
影响因子：
4.8
通讯作者：
Trefely, Sophie
中科院分区：
文献类型：
--
作者：
Soaita, Ioana;Megill, Emily;Kantner, Daniel;Chatoff, Adam;Cheong, Yuen Jian;Clarke, Philippa;Arany, Zoltan;Snyder, Nathaniel W.;Wellen, Kathryn E.;Trefely, Sophie
细胞储存和快速动员能量储备以应对营养供应的能力对生存至关重要。碳储存的分解产生乙酰辅酶A（AcCoA），其为必需的代谢途径提供燃料，也是蛋白质赖氨酸乙酰化的酰基供体。组蛋白是一种丰富的高度乙酰化的蛋白质，占细胞蛋白乙酰化的40%至75%。值得注意的是，组蛋白乙酰化对AcCoA的可用性敏感，并且营养物充足的条件诱导组蛋白上乙酰化的大量积累。脱乙酰化释放乙酸，其可以再循环到AcCoA，这表明脱乙酰化可以作为AcCoA来源被动员，以在营养物耗尽的情况下供给下游代谢过程。虽然组蛋白作为代谢储库的概念经常被提出，但缺乏实验证据。因此，为了直接测试这一概念，我们使用乙酸盐依赖性、ATP柠檬酸裂解酶缺陷的小鼠胚胎成纤维细胞（Acly−/− MEFs），并设计了一个脉冲追踪实验系统来追踪脱乙酰化衍生的乙酸盐及其掺入AcCoA。我们发现Acly−/− MEFs中的动态蛋白质脱乙酰化为AcCoA和近端下游代谢物提供了碳。然而，去乙酰化对酰基辅酶A库的大小没有显著影响，即使在最大乙酰化下，去乙酰化也短暂地提供了少于10%的细胞乙酰辅酶A。总之，我们的数据表明，尽管组蛋白乙酰化是动态的和营养敏感的，但与细胞需求相比，其维持细胞AcCoA依赖性代谢途径的潜力有限。
The ability of cells to store and rapidly mobilize energy reserves in response to nutrient availability is essential for survival. Breakdown of carbon stores produces acetyl-CoA (AcCoA), which fuels essential metabolic pathways and is also the acyl donor for protein lysine acetylation. Histones are abundant and highly acetylated proteins, accounting for 40% to 75% of cellular protein acetylation. Notably, histone acetylation is sensitive to AcCoA availability, and nutrient replete conditions induce a substantial accumulation of acetylation on histones. Deacetylation releases acetate, which can be recycled to AcCoA, suggesting that deacetylation could be mobilized as an AcCoA source to feed downstream metabolic processes under nutrient depletion. While the notion of histones as a metabolic reservoir has been frequently proposed, experimental evidence has been lacking. Therefore, to test this concept directly, we used acetate-dependent, ATP citrate lyase–deficient mouse embryonic fibroblasts (Acly−/− MEFs), and designed a pulse-chase experimental system to trace deacetylation-derived acetate and its incorporation into AcCoA. We found that dynamic protein deacetylation in Acly−/− MEFs contributed carbons to AcCoA and proximal downstream metabolites. However, deacetylation had no significant effect on acyl-CoA pool sizes, and even at maximal acetylation, deacetylation transiently supplied less than 10% of cellular AcCoA. Together, our data reveal that although histone acetylation is dynamic and nutrient-sensitive, its potential for maintaining cellular AcCoA-dependent metabolic pathways is limited compared to cellular demand.
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影响因子：
29
作者：
Lee JV;Carrer A;Shah S;Snyder NW;Wei S;Venneti S;Worth AJ;Yuan ZF;Lim HW;Liu S;Jackson E;Aiello NM;Haas NB;Rebbeck TR;Judkins A;Won KJ;Chodosh LA;Garcia BA;Stanger BZ;Feldman MD;Blair IA;Wellen KE
通讯作者：
Wellen KE
影响因子：
56.9
作者：
Choudhary, Chunaram;Kumar, Chanchal;Mann, Matthias
通讯作者：
Mann, Matthias
影响因子：
9.8
作者：
Church DM;Goodstadt L;Hillier LW;Zody MC;Goldstein S;She X;Bult CJ;Agarwala R;Cherry JL;DiCuccio M;Hlavina W;Kapustin Y;Meric P;Maglott D;Birtle Z;Marques AC;Graves T;Zhou S;Teague B;Potamousis K;Churas C;Place M;Herschleb J;Runnheim R;Forrest D;Amos-Landgraf J;Schwartz DC;Cheng Z;Lindblad-Toh K;Eichler EE;Ponting CP;Mouse Genome Sequencing Consortium
通讯作者：
Mouse Genome Sequencing Consortium
影响因子：
10.5
作者：
Lee JV;Berry CT;Kim K;Sen P;Kim T;Carrer A;Trefely S;Zhao S;Fernandez S;Barney LE;Schwartz AD;Peyton SR;Snyder NW;Berger SL;Freedman BD;Wellen KE
通讯作者：
Wellen KE
影响因子：
--
作者：
Koeller, KM;Haggarty, SJ;Schreiber, SL
通讯作者：
Schreiber, SL