PDF(Pubmed)
Abstract：
Macroautophagy, the mainly regulated form of autophagy, maintains the cellular homeostasis and degrades the transported cargoes. It is initiated by the protein kinase complex regulating by two signals pathway Mammalian target of rapamycin complex 1 (mTORC1)-Adenosine 5\' monophosphate activated protein kinase (AMPK)-Unc 51 like kinase 1(ULK1) and ULK1-PI3K- phosphatidylinositol 3-phosphate (PI3P). Currently, autolysosomes are accumulated during the aging process of CD8+T cells in vitro and may participate in inducing death sensitization of senescent cells. The main mechanism of aplastic anemia, a hyperimmune disease, is the T cells subsets imbalance such as CD8+T cells abnormal activation and hyperfunction. Therefore, the role of autophagy in the CD8+T cells and supposed whether some immunosuppress drugs induced the cells autophagic death to treat the hyperimmune diseases were focused. It was decided found that the acetyltransferase p300 obviously increased in the aplastic anemia patients and was related with the severity of disease. Previous studies have reported that canonical autophagy is regulated by the mTORC1-p300 axis. p300 is a critical bridge in the p300-VPS34 axis mediated non-canonical autophagy. There is the deficiency of autophagy and acetylation in the CD8+T cells. The expression of p300 also decreased notably after the immunosuppressive drugs therapy. Our findings provide a framework for understanding how immunosuppressive drugs effect on the AA autophagy deficiency mechanism and proved that immunosuppressive drugs negatively regulated the function of CD8+T cells by p300-mediated canonical autophagy pathway and non-canonical autophagy pathway.
摘要：
巨自噬,自噬的主要调节形式，维持细胞稳态并降解运输的货物。它由蛋白激酶复合物启动，通过两个信号通路调节哺乳动物雷帕霉素复合物1（mTORC1）-腺苷5'一磷酸活化蛋白激酶（AMPK）-Unc51样激酶1（ULK1）和ULK1-PI3K-磷脂酰肌醇3-磷酸（PI3P）。目前,自体溶酶体在体外CD8+T细胞的衰老过程中积累，并可能参与诱导衰老细胞的死亡敏化。再生障碍性贫血的主要机制,一种高免疫疾病，T细胞亚群失衡如CD8+T细胞异常活化和功能亢进。因此,自噬在CD8+T细胞中的作用以及某些免疫抑制药物是否诱导细胞自噬死亡以治疗高免疫性疾病成为研究热点。发现再生障碍性贫血患者的乙酰转移酶p300明显升高，并与疾病的严重程度有关。先前的研究已经报道，典型的自噬受mTORC1-p300轴的调节。p300是p300-VPS34轴介导的非经典自噬的关键桥。在CD8+T细胞中存在自噬和乙酰化的缺陷。在免疫抑制药物治疗后,p300的表达也显著降低。我们的发现为理解免疫抑制药物如何影响AA自噬缺乏机制提供了框架，并证明了免疫抑制药物通过p300介导的经典自噬途径和非经典自噬途径负调节CD8+T细胞的功能。
