Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California San Diego (UCSD), La Jolla, CA 92093-0723, USA.
Science. 2010 Mar 5;327(5970):1223-8. doi: 10.1126/science.1182228.
Sestrins are conserved proteins that accumulate in cells exposed to stress, potentiate adenosine monophosphate-activated protein kinase (AMPK), and inhibit activation of target of rapamycin (TOR). We show that the abundance of Drosophila sestrin (dSesn) is increased upon chronic TOR activation through accumulation of reactive oxygen species that cause activation of c-Jun amino-terminal kinase and transcription factor Forkhead box O (FoxO). Loss of dSesn resulted in age-associated pathologies including triglyceride accumulation, mitochondrial dysfunction, muscle degeneration, and cardiac malfunction, which were prevented by pharmacological activation of AMPK or inhibition of TOR. Hence, dSesn appears to be a negative feedback regulator of TOR that integrates metabolic and stress inputs and prevents pathologies caused by chronic TOR activation that may result from diminished autophagic clearance of damaged mitochondria, protein aggregates, or lipids.
Sestrins 是一种保守的蛋白质，在细胞受到应激时积累，增强单磷酸腺苷激活的蛋白激酶 (AMPK)，并抑制雷帕霉素靶蛋白 (TOR) 的激活。我们发现，通过积累活性氧引起 c-Jun 氨基末端激酶和转录因子叉头框 O (FoxO) 的激活，慢性 TOR 激活会导致果蝇 sestrin (dSesn) 的丰度增加。dSesn 的缺失导致与年龄相关的病理，包括甘油三酯积累、线粒体功能障碍、肌肉退化和心脏功能障碍，这些病理可以通过 AMPK 的药理学激活或 TOR 的抑制来预防。因此，dSesn 似乎是 TOR 的负反馈调节剂，它整合代谢和应激输入，并防止由慢性 TOR 激活引起的病理，这可能是由于受损线粒体、蛋白质聚集体或脂质的自噬清除减少所致。
