C/EBP-α induces autophagy by binding to Beclin1 through its own acetylation modification in activated hepatic stellate cells
C/EBP-α induces autophagy by binding to Beclin1 through its own acetylation modification in activated hepatic stellate cells
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C/EBP-alpha 在活化的肝星状细胞中通过其自身的乙酰化修饰与 Beclin1 结合来诱导自噬
DOI：
10.1016/j.yexcr.2021.112721
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发表时间：
2021-07-13
影响因子：
3.7
通讯作者：
Liu, Xiuping
中科院分区：
文献类型：
--
作者：
Hou, Chenjian;Lu, Shan;Liu, Xiuping
肝星状细胞（hepatic stellate cells, hsc）的活化在肝纤维化的发生中起着关键作用，促进活化的hsc凋亡或减少活化的hsc数量可以逆转肝纤维化的发展。在我们之前的研究中，我们已经证明了CCAAT/增强子结合蛋白α (C/ ebp - α)在促进活化的hsc凋亡中发挥重要作用，从而起到抗肝纤维化的作用。与细胞凋亡不同，自噬作为一种不依赖caspase的程序性细胞死亡，可以迅速清除细胞内物质的异常积累或受损细胞器，在调节细胞内环境的稳态中发挥关键作用。然而，C/EBP-alpha是否参与造血干细胞自噬的发生尚不清楚。因此，在本研究中，我们首先采用Western blot和免疫荧光的方法来表征C/EBP-alpha过表达对造血干细胞中与自噬相关的LC3B、P62、ATG5和Beclin1蛋白表达的影响。随后，我们通过Western blot和定点诱变的方法来明确C/ ebp - α诱导自噬的类型和相关机制。本研究表明，C/ ebp - α促进造血干细胞自噬的发生，C/ ebp - α诱导的自噬属于有丝自噬。C/ ebp - α蛋白的稳定性调节造血干细胞的自噬水平。此外，C/ ebp - α的乙酰化也调节造血干细胞自噬的发生。赖氨酸在C/EBP-alpha的K298、K302和K326位点的乙酰化促进了它与Beclin1的结合。总之，我们的研究揭示了C/ ebp - α在调节造血干细胞自噬中的作用，从而为临床治疗肝纤维化提供了新的策略。
The activation of hepatic stellate cells (HSCs) plays a key role in the occurrence of liver fibrosis,and promoting the apoptosis of activated HSCs or reducing the number of activated HSCs can reverse the development of liver fibrosis. In our previous studies, we have demonstrated that the CCAAT/enhancer binding protein alpha (C/EBP-alpha) played an important role in promoting the apoptosis of activated HSCs, thereby exerting an anti-liver fibrosis effect. Unlike apoptosis, autophagy, as a caspase-independent programmed cell death, can promptly remove the abnormal accumulation of substances or damaged organelles in cells and play a key role in regulating the homeostasis of intracellular environment. However, it is still unclear whether C/EBP-alpha participates in the occurrence of autophagy in HSCs. Therefore, in this study, we firstly used the methods of Western blot and immunofluorescence to characterize the consequence of C/EBP-alpha overexpression on the expression of proteins LC3B, P62, ATG5 and Beclin1 which were related to autophagy in HSCs. Subsequently, we performed Western blot and site-directed mutagenesis methods to clarify the type and related mechanism of autophagy which was induced by C/EBP-alpha. Here we show that C/EBP-alpha promotes the occurrence of autophagy in HSCs and the autophagy induced by C/EBP-alpha belongs to mitophagy. The stability of C/EBP-alpha protein regulates the level of autophagy in HSCs. In addition, acetylation of C/EBP-alpha also regulates the occurrence of autophagy in HSCs. Acetylation of lysine at positions K298, K302 and K326 of C/EBP-alpha promotes its binding to Beclin1. In conclusion, our study uncovers the role of C/EBP-alpha in regulating autophagy in HSCs, thereby providing a new strategy for clinical treatment of liver fibrosis.