Cholesterol derivatives induce dephosphorylation of the histone deacetylases Rpd3/HDAC1 to upregulate autophagy
Cholesterol derivatives induce dephosphorylation of the histone deacetylases Rpd3/HDAC1 to upregulate autophagy
复制标题
胆固醇衍生物诱导组蛋白脱乙酰酶 Rpd3/HDAC1 去磷酸化，上调自噬
DOI：
10.1080/15548627.2020.1725376
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发表时间：
2020-02-14
期刊：
影响因子：
13.3
通讯作者：
Tian，Ling
中科院分区：
文献类型：
--
作者：
Wu，Wenmei;Luo，Man;Tian，Ling
组蛋白去乙酰化酶（hdac）对全球基因表达很重要，并有助于许多生理事件。酵母脱乙酰酶Rpd3及其保守同源物HDAC1在哺乳动物中反向调控自噬；然而，Rpd3/HDAC1如何调节介导自噬尚不清楚。在这里，我们发现家蚕（Bombyx mori）的自噬发生需要BmRpd3，其中类固醇激素20-羟基蜕皮激素（20E）信号负调控其蛋白水平和核定位。抑制MTOR导致BmRpd3/HsHDAC1的去磷酸化和核-胞质易位。此外，胆固醇、20E和27-羟基胆固醇均可通过影响MTORC1活性诱导BmRpd3/HsHDAC1大量去磷酸化和胞质定位，从而导致自噬。此外，在BmRpd3中鉴定的三个磷酸化位点（Ser392， Ser421和Ser423）在HsHDAC1中保守。单个或三个磷酸化位点突变降低了BmRpd3/HsHDAC1的磷酸化水平，导致其细胞质定位和自噬激活。一般来说，胆固醇衍生物，特别是羟基化胆固醇，通过抑制MTOR信号传导促进b的自噬，引起BmRpd3/HsHDAC1的去磷酸化和核胞质穿梭。moriand哺乳动物。这些发现提高了我们对胆固醇衍生物诱导的BmRpd3/ hshdac1介导的自噬的理解，并揭示了它们作为神经退行性疾病和自噬相关研究的治疗靶点的潜力。缩写:20 e: 20-hydroxyecdysone;27-OH: 27-hydroxycholesterol;ACTB：肌动蛋白；AMPK: amp活化蛋白激酶；Atg: autophagy-related;BmSqstm1: Bombyxsequestosome 1;CQ:氯喹;HDAC：组蛋白脱乙酰酶；LMNB：层粘连蛋白B1；MTOR：雷帕霉素激酶的机制靶点体育:磷脂酰乙醇胺;SQSTM1/p62: sequestosome 1；TUBA1A：微管蛋白α 1a。
Histone deacetylases (HDACs) are important for global gene expression and contribute to numerous physiological events. Deacetylase Rpd3 in yeast and its conserved homolog HDAC1 in mammals oppositely regulate autophagy; however, how Rpd3/HDAC1 is regulated to mediate autophagy remains unclear. Here, we showed autophagy occurrence in silkworm (Bombyx mori) required BmRpd3, wherein steroid hormone 20-hydroxyecdysone (20E) signaling regulated its protein level and nuclear localization negatively. Inhibition of MTOR led to dephosphorylation and nucleo-cytoplasmic translocation of BmRpd3/HsHDAC1. Besides, cholesterol, 20E, and 27-hydroxycholesterol could all induce massive dephosphorylation and cytoplasmic localization of BmRpd3/HsHDAC1, and thus autophagy by affecting MTORC1 activity. In addition, three phosphorylation sites (Ser392, Ser421, and Ser423) identified in BmRpd3 were conserved in HsHDAC1. Single or triple phosphorylation-site mutation attenuated the phosphorylation levels of BmRpd3/HsHDAC1, leading to their cytoplasmic localization and autophagy activation. In general, cholesterol derivatives, especially hydroxylated cholesterol, caused dephosphorylation and nucleo-cytoplasmic shuttling of BmRpd3/HsHDAC1 through inhibition of MTOR signaling to facilitate autophagy inB. moriand mammals. These findings improve our understandings of BmRpd3/HsHDAC1-mediated autophagy induced by cholesterol derivatives and shed light on their potential as a therapeutic target for neurodegenerative diseases and autophagy-related studies.Abbreviations:20E: 20-hydroxyecdysone; 27-OH: 27-hydroxycholesterol; ACTB: actin beta; AMPK: AMP-activated protein kinase; Atg: autophagy-related; BmSqstm1:Bombyxsequestosome 1; CQ: chloroquine; HDAC: histone deacetylase; LMNB: Lamin B1; MTOR: mechanistic target of rapamycin kinase; PE: phosphatidylethanolamine; SQSTM1/p62: sequestosome 1; TUBA1A: tubulin alpha 1a.