Drosophila Sirt2/mammalian SIRT3 deacetylates ATP synthase β and regulates complex V activity.
Drosophila Sirt2/mammalian SIRT3 deacetylates ATP synthase β and regulates complex V activity.
复制标题
DOI：
10.1083/jcb.201404118
复制
发表时间：
2014-07-21
期刊：
影响因子：
--
通讯作者：
Acharya UR
中科院分区：
文献类型：
--
作者：
Rahman M;Nirala NK;Singh A;Zhu LJ;Taguchi K;Bamba T;Fukusaki E;Shaw LM;Lambright DG;Acharya JK;Acharya UR
Sirtuin介导的线粒体复合体V催化亚基的脱乙酰化增加了复合体的活性。三磷酸腺苷合成酶β是线粒体复合体V的催化亚单位，合成三磷酸腺苷。我们发现三磷酸腺苷合成酶β是由依赖于人烟酰胺腺嘌呤二核苷酸(NAD+)的蛋白质去乙酰化的Sirtuin3及其果蝇的黑腹果蝇同源物dSirt2来脱乙酰化的。Dsirt2突变的果蝇表现出β合成酶中特定赖氨酸残基的乙酰化增加和复合体V活性的降低。DSirt2过表达可增加复合体V的活性。人三磷酸腺苷合成酶β中的赖氨酸259和赖氨酸480用精氨酸代替，模拟脱乙酰基，增加了复合体V的活性，而用谷氨酰胺代替，模拟乙酰化，活性降低。野生型和dsirt2线粒体的质谱学和蛋白质组学实验证实了果蝇线粒体的乙酰化组，并揭示了dSirt2是线粒体能量代谢的重要调节因子。此外，我们还揭示了神经酰胺-NAD+-sirtuin轴，其中神经酰胺的增加导致NAD+的耗竭，从而导致sirtuin活性的降低。神经酰胺是一种已知的诱导应激反应的鞘磷脂。这些结果为sirtuin介导的复合体V的调节提供了洞察力，并揭示了神经酰胺和果蝇乙酰组之间的新联系。
Sirtuin-mediated deacetylation of the catalytic subunit of mitochondrial complex V increases complex activity. Adenosine triphosphate (ATP) synthase β, the catalytic subunit of mitochondrial complex V, synthesizes ATP. We show that ATP synthase β is deacetylated by a human nicotinamide adenine dinucleotide (NAD+)–dependent protein deacetylase, sirtuin 3, and its Drosophila melanogaster homologue, dSirt2. dsirt2 mutant flies displayed increased acetylation of specific Lys residues in ATP synthase β and decreased complex V activity. Overexpression of dSirt2 increased complex V activity. Substitution of Lys 259 and Lys 480 with Arg in human ATP synthase β, mimicking deacetylation, increased complex V activity, whereas substitution with Gln, mimicking acetylation, decreased activity. Mass spectrometry and proteomic experiments from wild-type and dsirt2 mitochondria identified the Drosophila mitochondrial acetylome and revealed dSirt2 as an important regulator of mitochondrial energy metabolism. Additionally, we unravel a ceramide–NAD+–sirtuin axis wherein increased ceramide, a sphingolipid known to induce stress responses, resulted in depletion of NAD+ and consequent decrease in sirtuin activity. These results provide insight into sirtuin-mediated regulation of complex V and reveal a novel link between ceramide and Drosophila acetylome.
登录
查看更多内容
影响因子：
56.9
作者：
Choudhary, Chunaram;Kumar, Chanchal;Mann, Matthias
通讯作者：
Mann, Matthias
肿瘤抑制因子 SIRT3 脱乙酰并激活锰超氧化物歧化酶清除 ROS
影响因子：
7.7
作者：
Chen, Yaohui;Zhang, Jinye;Lin, Yan;Lei, Qunying;Guan, Kun-Liang;Zhao, Shimin;Xiong, Yue
通讯作者：
Xiong, Yue
DOI：
10.1146/annurev.pathol.4.110807.092250
发表时间：
2010
期刊：
Annual review of pathology
影响因子：
--
作者：
Haigis MC;Sinclair DA
通讯作者：
Sinclair DA
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y
影响因子：
13.8
作者：
Imai S;Guarente L
通讯作者：
Guarente L