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AMPK-SKP2-CARM1 signalling cascade in transcriptional regulation of autophagy

机译：AMPK-SKP2-CARM1信号转导在自噬转录调控中的作用

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摘要

Autophagy is a highly conserved self-digestion process, which is essential for maintaining homeostasis and viability in response to nutrient starvation(1-4). Although the components of autophagy in the cytoplasm have been well studied(5,6), the molecular basis for the transcriptional and epigenetic regulation of autophagy is poorly understood. Here we identify co-activator-associated arginine methyltransferase 1 (CARM1) as a crucial component of autophagy in mammals. Notably, CARM1 stability is regulated by the SKP2-containing SCF (SKP1-cullin1-F-box protein) E3 ubiquitin ligase in the nucleus, but not in the cytoplasm, under nutrient-rich conditions. Furthermore, we show that nutrient starvation results in AMP-activated protein kinase (AMPK)-dependent phosphorylation of FOXO3a in the nucleus, which in turn transcriptionally represses SKP2. This repression leads to increased levels of CARM1 protein and subsequent increases in histone H3 Arg17 dimethylation. Genome-wide analyses reveal that CARM1 exerts transcriptional co-activator function on autophagy-related and lysosomal genes through transcription factor EB (TFEB). Our findings demonstrate that CARM1-dependent histone arginine methylation is a crucial nuclear event in autophagy, and identify a new signalling axis of AMPK-SKP2-CARM1 in the regulation of autophagy induction after nutrient starvation.
机译：自噬是一个高度保守的自我消化过程，对于维持营养平衡和营养平衡而言，这对于维持体内平衡和生存至关重要（1-4）。尽管自噬在细胞质中的组成已得到了很好的研究（5,6），但对自噬的转录和表观遗传调控的分子基础了解甚少。在这里，我们确定了共激活因子相关的精氨酸甲基转移酶1（CARM1）是哺乳动物自噬的重要组成部分。值得注意的是，在营养丰富的条件下，CARM1的稳定性受含SKP2的SCF（SKP1-cullin1-F-box蛋白）E3泛素连接酶的调节，而不是在细胞质中。此外，我们显示营养饥饿导致细胞核中FOXO3a的AMP激活蛋白激酶（AMPK）依赖性磷酸化，进而转录抑制SKP2。这种抑制导致CARM1蛋白水平升高，随后组蛋白H3 Arg17二甲基化水平升高。全基因组分析表明，CARM1通过转录因子EB（TFEB）在自噬相关基因和溶酶体基因上发挥转录共激活子功能。我们的发现表明，依赖CARM1的组蛋白精氨酸甲基化是自噬中的关键核事件，并确定了营养饥饿后自噬诱导调控中AMPK-SKP2-CARM1的新信号转导轴。

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  • 来源
    《Nature》 |2016年第7608期|553-557|共5页
  • 作者

    Shin Hi-Jai R.; Kim Hyunkyung; Oh Sungryong; Lee Jun-Gi; Kee Minjung; Ko Hyun-Jeong; Kweon Mi-Na; Won Kyoung-Jae; Baek Sung Hee;

  • 作者单位

    Seoul Natl Univ, Sch Biol Sci, Creat Res Initiat Ctr Chromatin Dynam, Seoul, South Korea;

    Seoul Natl Univ, Sch Biol Sci, Creat Res Initiat Ctr Chromatin Dynam, Seoul, South Korea;

    Seoul Natl Univ, Sch Biol Sci, Creat Res Initiat Ctr Chromatin Dynam, Seoul, South Korea;

    Seoul Natl Univ, Sch Biol Sci, Creat Res Initiat Ctr Chromatin Dynam, Seoul, South Korea;

    Seoul Natl Univ, Sch Biol Sci, Creat Res Initiat Ctr Chromatin Dynam, Seoul, South Korea;

    Kangwon Natl Univ, Coll Pharm, Lab Microbiol & Immunol, Chunchon, South Korea;

    Univ Ulsan, Coll Med, Asan Med Ctr, Mucosal Immunol Lab,Dept Convergence Med, Seoul, South Korea;

    Univ Penn, Perelman Sch Med, Dept Genet, Inst Diabet Obes & Metab, Philadelphia, PA 19104 USA;

    Seoul Natl Univ, Sch Biol Sci, Creat Res Initiat Ctr Chromatin Dynam, Seoul, South Korea;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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