亚精胺诱导自噬的作用机制

亚精胺(spermidine)是含有3个胺基的低分子量脂肪族碳化物,是存在于所有生物体中的天然多胺之一。自噬(autophagy)对于降解细胞内受损蛋白质和细胞器是必需的。外源性亚精胺可作为自噬的天然诱导剂,并且是安全和无毒的。新近研究表明,亚精胺可通过AKT/AMPK-FoxO3-Atg途径诱导自噬,还能促进组蛋白脱乙酰基酶4(histone deacetylase 4,HDAC4)向细胞核转运,降低细胞质HDAC4含量,进而增强微管相关蛋白1S(microtubule-associated protein 1S,MAP1S)乙酰化和稳定性以激活自噬。此外,亚精胺可作为乙酰转移酶抑制剂调节EP300活性,进而改变Atg5、Atg7、LC3和Atg12的乙酰化状态。同时,还可通过诱导哺乳动物雷帕霉素靶蛋白(mammalian target of rapamycin,mTOR)去磷酸化,激活ULK1/2-Atg13-FIP200复合物参与调控动物机体内的自噬过程。本文就自噬概念和亚精胺诱导自噬作用途径的最新研究进展作一综述。

Mechanism of Autophagy Induced by Spermidine

Spermidine has a low molecular weight and can be defined by aliphatic carbon chains including three amino groups. It is one of the natural polyamines found in all living organisms. Autophagy is necessary to the cell and organism because it eliminates potentially harmful proteins and damaged organelles. Exogenous spermidine can be used as a natural inducer of autophagy and is safe and non-toxic. Recent studies have shown that spermidine induces autophagy with a variety of strategies, namely by (i) Inducing autophagy through the AKT/AMPK-FoxO3-Atg pathways, (ii) Accelerating the transport of histone deacetylase 4 (HDAC4) into the nucleus, in turn decreasing HDAC4 levels in the cytoplasm and enhancing the acetylation and stability of microtubule-associated protein 1S(MAP1S), (iii) Acting as an acetyltransferase inhibitor which can regulate the activity of EP300, thereby mediating the acetylation state of Atg5, Atg7, LC3 and Atg12, (iv) Inducing the dephosphorylation of mammalian target of rapamycin (mTOR) and activating Ulk1/2-Atg13-FIP200 complex. In this paper, the concept of autophagy and the latest research progress in the pathway of autophagy induced by spermidine are reviewed.