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Dynamic Regulation of ME1 Phosphorylation and Acetylation Affects Lipid Metabolism and Colorectal Tumorigenesis.
Molecular Cell ( IF 14.5 ) Pub Date : 2019-11-14 , DOI: 10.1016/j.molcel.2019.10.015 Yahui Zhu 1 , Li Gu 1 , Xi Lin 1 , Cheng Liu 1 , Bingjun Lu 1 , Kaisa Cui 1 , Feng Zhou 2 , Qiu Zhao 2 , Edward V Prochownik 3 , Chengpeng Fan 4 , Youjun Li 1
Molecular Cell ( IF 14.5 ) Pub Date : 2019-11-14 , DOI: 10.1016/j.molcel.2019.10.015 Yahui Zhu 1 , Li Gu 1 , Xi Lin 1 , Cheng Liu 1 , Bingjun Lu 1 , Kaisa Cui 1 , Feng Zhou 2 , Qiu Zhao 2 , Edward V Prochownik 3 , Chengpeng Fan 4 , Youjun Li 1
Affiliation
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PGAM5 is a mitochondrial serine/threonine phosphatase that regulates multiple metabolic pathways and contributes to tumorigenesis in a poorly understood manner. We show here that PGAM5 inhibition attenuates lipid metabolism and colorectal tumorigenesis in mice. PGAM5-mediated dephosphorylation of malic enzyme 1 (ME1) at S336 allows increased ACAT1-mediated K337 acetylation, leading to ME1 dimerization and activation, both of which are reversed by NEK1 kinase-mediated S336 phosphorylation. SIRT6 deacetylase antagonizes ACAT1 function in a manner that involves mutually exclusive ME1 S336 phosphorylation and K337 acetylation. ME1 also promotes nicotinamide adenine dinucleotide phosphate (NADPH) production, lipogenesis, and colorectal cancers in which ME1 transcripts are upregulated and ME1 protein is hypophosphorylated at S336 and hyperacetylated at K337. PGAM5 and ME1 upregulation occur via direct transcriptional activation mediated by β-catenin/TCF1. Thus, the balance between PGAM5-mediated dephosphorylation of ME1 S336 and ACAT1-mediated acetylation of K337 strongly influences NADPH generation, lipid metabolism, and the susceptibility to colorectal tumorigenesis.
中文翻译：
ME1磷酸化和乙酰化的动态调节影响脂质代谢和结直肠肿瘤发生。
PGAM5是一种线粒体丝氨酸/苏氨酸磷酸酶，可调节多种代谢途径，并以人们不太了解的方式促进肿瘤发生。我们在这里显示PGAM5抑制作用会减弱小鼠的脂质代谢和结肠直肠肿瘤的发生。PGAM5介导的S336苹果酸酶1（ME1）的去磷酸化增加了ACAT1介导的K337乙酰化作用，导致ME1二聚化和活化，两者均被NEK1激酶介导的S336磷酸化所逆转。SIRT6脱乙酰基酶以相互排斥的ME1 S336磷酸化和K337乙酰化的方式拮抗ACAT1的功能。ME1还促进烟酰胺腺嘌呤二核苷酸磷酸（NADPH）的产生，脂肪生成，在大肠癌中，ME1转录本被上调，ME1蛋白在S336处被磷酸化，而在K337处被过度乙酰化。PGAM5和ME1的上调通过β-catenin/ TCF1介导的直接转录激活而发生。因此，PGAM5介导的ME1 S336的去磷酸化和ACAT1介导的K337的乙酰化之间的平衡强烈影响NADPH的产生，脂质代谢以及对结直肠肿瘤发生的敏感性。
更新日期：2019-11-14
中文翻译：
ME1磷酸化和乙酰化的动态调节影响脂质代谢和结直肠肿瘤发生。
PGAM5是一种线粒体丝氨酸/苏氨酸磷酸酶，可调节多种代谢途径，并以人们不太了解的方式促进肿瘤发生。我们在这里显示PGAM5抑制作用会减弱小鼠的脂质代谢和结肠直肠肿瘤的发生。PGAM5介导的S336苹果酸酶1（ME1）的去磷酸化增加了ACAT1介导的K337乙酰化作用，导致ME1二聚化和活化，两者均被NEK1激酶介导的S336磷酸化所逆转。SIRT6脱乙酰基酶以相互排斥的ME1 S336磷酸化和K337乙酰化的方式拮抗ACAT1的功能。ME1还促进烟酰胺腺嘌呤二核苷酸磷酸（NADPH）的产生，脂肪生成，在大肠癌中，ME1转录本被上调，ME1蛋白在S336处被磷酸化，而在K337处被过度乙酰化。PGAM5和ME1的上调通过β-catenin/ TCF1介导的直接转录激活而发生。因此，PGAM5介导的ME1 S336的去磷酸化和ACAT1介导的K337的乙酰化之间的平衡强烈影响NADPH的产生，脂质代谢以及对结直肠肿瘤发生的敏感性。
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