Activation of the AMPK-ULK1 pathway plays an important role in autophagy during prion infection.
Activation of the AMPK-ULK1 pathway plays an important role in autophagy during prion infection.
复制标题
AMPK-ULK1 通路的激活在朊病毒感染期间的自噬中发挥重要作用。
DOI：
10.1038/srep14728
复制
发表时间：
2015-10-01
影响因子：
4.6
通讯作者：
Dong XP
中科院分区：
文献类型：
--
作者：
Fan XY;Tian C;Wang H;Xu Y;Ren K;Zhang BY;Gao C;Shi Q;Meng G;Zhang LB;Zhao YJ;Shao QX;Dong XP
AMPK是一种丝氨酸/苏氨酸蛋白激酶，通过在特定位点磷酸化ULK 1，作为自噬的正调节因子。先前的一项研究表明，在痒病感染的实验啮齿动物和某些人类朊病毒疾病中，巨自噬系统被激活，其中重要的负调节因子mTOR被严重抑制。在这项研究中，AMPK和ULK 1感染羊瘙痒症菌株263 K和羊瘙痒症感染的细胞系SMB-S15的仓鼠的大脑进行了分析。结果显示AMPK和AMPK-Thr 172、ULK 1和ULK 1-Ser 555表达呈上调趋势。脑AMPK和ULK 1的增加发生在263 K感染的早期阶段。磷酸化ULK 1-Ser 757的水平在感染中期下降，并且仅在终末期可忽略不计地存在，这种模式表明磷酸化蛋白与改变的内源性mTOR的密切关系。此外，与AMPK激活相关的LKB 1水平在感染的早期和中期选择性增加。在SMB-S15细胞中内源性ULK 1的敲低抑制LC 3脂化。这些结果表明，除了mTOR调节途径的废除外，朊病毒感染期间AMPK-ULK 1途径的激活还有助于朊病毒感染脑组织中的自噬激活。
AMPK is a serine/threonine protein kinase that acts as a positive regulator of autophagy, by phosphorylating ULK1 at specific sites. A previous study demonstrated activation of the macroautophagic system in scrapie-infected experimental rodents and in certain human prion diseases, in which the essential negative regulator mTOR is severely inhibited. In this study, AMPK and ULK1 in the brains of hamsters infected with scrapie strain 263 K and in the scrapie-infected cell line SMB-S15 were analysed. The results showed an up-regulated trend of AMPK and AMPK-Thr172, ULK1 and ULK1-Ser555. Increases in brain AMPK and ULK1 occurred at an early stage of agent 263 K infection. The level of phosphorylated ULK1-Ser757 decreased during mid-infection and was only negligibly present at the terminal stage, a pattern that suggested a close relationship of the phosphorylated protein with altered endogenous mTOR. In addition, the level of LKB1 associated with AMPK activation was selectively increased at the early and middle stages of infection. Knockdown of endogenous ULK1 in SMB-S15 cells inhibited LC3 lipidation. These results showed that, in addition to the abolishment of the mTOR regulatory pathway, activation of the AMPK-ULK1 pathway during prion infection contributes to autophagy activation in prion-infected brain tissues.