Zada Sahib, Noh Hae Sook, Baek Seon Mi, Ha Ji Hye, Hahm Jong Ryeal, Kim Deok Ryong
Department of Biochemistry and Convergence Medical Sciences, Gyeongsang National University School of Medicine, JinJu, Republic of Korea.
Institute of Health Sciences, Gyeongsang National University School of Medicine, JinJu, Republic of Korea.
Cell Biol Int. 2015 Nov;39(11):1242-50. doi: 10.1002/cbin.10497. Epub 2015 Jul 15.
The MAPK and mTOR signal pathways in endosomes or lysosomes play a crucial role in cell survival and death. They are also closely associated with autophagy, a catabolic process highly regulated under various cellular stress or nutrient deprivation. Recently we have isolated a protein, named p18/LAMTOR1, that specifically regulates the ERK or mTOR pathway in lysosomes. p18/LAMTOR1 also interacts with p27(kip1) . Here we examined how p18/LAMTOR1 plays a role in autophagy under nutrient deprivation. The p18(+/+) MEF cells were more susceptible to cell death under starvation or in the presence of AICAR in comparison with p18(-/-) MEF cells. Cleavage of caspase-3 was increased in p18(+/+) MEF cells under starvation, and phosphorylation at the threonine 198 of p27(kip1) was highly elevated in starved p18(-/-) MEF cells. Furthermore, LC3-II formation and other autophagy-associated proteins were largely increased in p18-deficient cells, and suppression of p27(kip1) expression in p18(-/-) MEF cells mitigated starvation-induced cell death. These data suggest that ablation of p18/LAMTOR1 suppresses starvation-induced cell death by stimulating autophagy through modulation of p27(kip1) activity.
内体或溶酶体中的丝裂原活化蛋白激酶（MAPK）和雷帕霉素靶蛋白（mTOR）信号通路在细胞存活和死亡中起关键作用。它们还与自噬密切相关，自噬是一种在各种细胞应激或营养剥夺情况下受到高度调控的分解代谢过程。最近，我们分离出一种名为p18/LAMTOR1的蛋白质，它特异性调节溶酶体中的细胞外信号调节激酶（ERK）或mTOR通路。p18/LAMTOR1还与p27（kip1）相互作用。在此，我们研究了p18/LAMTOR1在营养剥夺情况下如何在自噬中发挥作用。与p18（-/-）小鼠胚胎成纤维细胞（MEF）相比，p18（+/ +）MEF细胞在饥饿状态下或存在5-氨基咪唑-4-甲酰胺核苷（AICAR）时更容易发生细胞死亡。在饥饿状态下，p18（+/ +）MEF细胞中半胱天冬酶-3的切割增加，而在饥饿的p18（-/-）MEF细胞中，p27（kip1）苏氨酸198位点的磷酸化水平显著升高。此外，在p18缺陷细胞中，微管相关蛋白1轻链3-II（LC3-II）的形成和其他自噬相关蛋白大量增加，并且在p18（-/-）MEF细胞中抑制p27（kip1）的表达可减轻饥饿诱导的细胞死亡。这些数据表明，p18/LAMTOR1的缺失通过调节p27（kip1）的活性刺激自噬，从而抑制饥饿诱导的细胞死亡。
