SIRT5 Regulates both Cytosolic and Mitochondrial Protein Malonylation with Glycolysis as a Major Target.
SIRT5 Regulates both Cytosolic and Mitochondrial Protein Malonylation with Glycolysis as a Major Target.
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DOI：
10.1016/j.molcel.2015.05.022
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发表时间：
2015-07-16
期刊：
影响因子：
16
通讯作者：
Verdin E
中科院分区：
文献类型：
--
作者：
Nishida Y;Rardin MJ;Carrico C;He W;Sahu AK;Gut P;Najjar R;Fitch M;Hellerstein M;Gibson BW;Verdin E
蛋白质酰化将能量底物通量与细胞适应性反应联系起来。SIRT 5是NAD+依赖性赖氨酸脱酰酶，并去除琥珀酰基和丙二酰基。使用亲和富集和无标记定量蛋白质组学，我们表征了野生型（WT）和Sirt 5 −/−小鼠中SIRT 5调节的赖氨酸丙二酸组。在430种蛋白质中鉴定了1，137个丙二酰赖氨酸位点，其中183个位点（来自120种蛋白质）在Sirt 5 −/−动物中显著增加。通路分析确定糖酵解是SIRT 5调节的最重要通路。重要的是，与WT小鼠相比，Sirt 5 −/−的原代肝细胞中的糖酵解通量减少。取代丙二酰赖氨酸残基184甘油醛3-磷酸脱氢酶与谷氨酸，丙二酰赖氨酸模拟物，抑制其酶活性。与我们以前关于酰化的报道相比，丙二酰化作用靶向的蛋白质与乙酰化和琥珀酰化作用不同。这些数据表明，SIRT 5是赖氨酸丙二酰化的全局调节剂，并提供了通过糖酵解调节能量通量的机制。
Protein acylation links energetic substrate flux with cellular adaptive responses. SIRT5 is a NAD+-dependent lysine deacylase and removes both succinyl and malonyl groups. Using affinity enrichment and label free quantitative proteomics, we characterized the SIRT5-regulated lysine malonylome in wild-type (WT) and Sirt5−/− mice. 1,137 malonyllysine sites were identified across 430 proteins, with 183 sites (from 120 proteins) significantly increased in Sirt5−/− animals. Pathway analysis identified glycolysis as the top SIRT5-regulated pathway. Importantly, glycolytic flux was diminished in primary hepatocytes from Sirt5−/− compared to WT mice. Substitution of malonylated lysine residue 184 in glyceraldehyde 3-phosphate dehydrogenase with glutamic acid, a malonyllysine mimic, suppressed its enzymatic activity. Comparison with our previous reports on acylation reveals that malonylation targets a different set of proteins than acetylation and succinylation. These data demonstrate that SIRT5 is a global regulator of lysine malonylation and provide a mechanism for regulation of energetic flux through glycolysis.