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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Ammonia-induced autophagy is independent of ULK1/ULK2 kinases
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Ammonia-induced autophagy is independent of ULK1/ULK2 kinases

机译：氨诱导的自噬独立于ULK1 / ULK2激酶

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摘要

Autophagy, a lysosome-mediated catabolic process, contributes to maintenance of intracellular homeostasis and cellular response to metabolic stress. In yeast, genes essential to the execution of autophagy have been defined, including autophagy-related gene 1 (ATG1), a kinase responsible for initiation of autophagy down stream of target of rapamycin. Here we investigate the role of the mammalian Atg1 homologs, uncoordinated family member (unc) 51-like kinase 1 and 2 (ULK1 and ULK2), in autophagy by gener ating mouse embryo fibroblasts (MEFs) doubly deficient for ULK1 and ULK2. We found that ULK1/2 are required in the autophagy response to amino acid deprivation but not for autophagy induced by deprivation of glucose or inhibition of glucose metabolism. This ULK1/2-independent autophagy was not the simple result of bio energetic compromise and failed to be induced by AMP-activated protein kinase activators such as 5-aminoimidazole-4-carboxamide riboside and phenformin. Instead we found that autophagy induc tion upon glucose deprivation correlated with a rise in cellular am monia levels caused by elevated amino acid catabolism. Even in complete medium, ammonia induced autophagy in WT and Ulk1/ 2-/- MEFs but not in Atg5-deficient MEFs. The autophagy response to ammonia is abrogated by a cell-permeable form of pyruvate resulting from the scavenging of excess ammonia through pyruvate conversion to alanine. Thus, although ULK1 and/or ULK2 are required for the autophagy response following deprivation of nitrogenous amino acids, the autophagy response to the enhanced amino acid catabolism induced by deprivation of glucose or direct exposure to ammonia does not require ULK1 and/or ULK2. Together, these data suggest that autophagy provides cells with a mechanism to adapt not only to nitrogen deprivation but also to nitrogen excess.
机译：自噬是一种溶酶体介导的分解代谢过程，有助于维持细胞内稳态和细胞对代谢应激的反应。在酵母中，已经定义了执行自噬必不可少的基因，包括自噬相关基因1（ATG1），一种负责引发雷帕霉素靶位下游自噬的激酶。在这里，我们通过产生对ULK1和ULK2双重缺乏的小鼠胚胎成纤维细胞（MEF），研究了哺乳动物Atg1同源物，不协调的家族成员（unc）51样激酶1和2（ULK1和ULK2）在自噬中的作用。我们发现ULK1 / 2是必需的自噬反应对氨基酸剥夺，而不是由于缺少葡萄糖或抑制葡萄糖代谢而引起的自噬。这种不依赖ULK1 / 2的自噬不是生物能量折衷的简单结果，并且不能被AMP激活的蛋白激酶激活剂（如5-氨基咪唑-4-羧酰胺核糖核苷和苯乙双胍）诱导。相反，我们发现对葡萄糖剥夺的自噬诱导与氨基酸分解代谢升高引起的细胞氨水平升高相关。即使在完全培养基中，氨也会在WT和Ulk1 / 2-/-MEF中诱导自噬，而在Atg5缺失的MEF中则不会。氨水的自噬反应被丙酮酸的细胞可渗透形式消除，这是由于丙酮酸转化为丙氨酸而清除了过量的氨。因此，尽管缺少含氮氨基酸后自噬反应需要ULK1和/或ULK2，但对因缺少葡萄糖或直接暴露于氨引起的增强的氨基酸分解代谢的自噬反应不需要ULK1和/或ULK2。总之，这些数据表明自噬为细胞提供了不仅适应氮缺乏而且适应氮过量的机制。

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