Withdrawal of Essential Amino Acids Increases Autophagy by a Pathway Involving Ca2+/Calmodulin-dependent Kinase Kinase-β (CaMKK-β)

被引:98
|
作者
Ghislat, Ghita [1 ,2 ]
Patron, Maria [3 ]
Rizzuto, Rosario [3 ]
Knecht, Erwin [1 ,2 ]
机构
[1] Ctr Invest Principe Felipe, Lab Biol Celular, Valencia 46012, Spain
[2] CIBERER, Valencia 46012, Spain
[3] Univ Padua, Dept Biomed Sci, I-35131 Padua, Italy
关键词
ACTIVATED PROTEIN-KINASE; HUMAN FIBROBLASTS; MAMMALIAN-CELLS; MTOR; PHOSPHORYLATION; CALCIUM; APOPTOSIS; ULK1; AMPK; MACROAUTOPHAGY;
D O I
10.1074/jbc.M112.365767
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Autophagy is the main lysosomal catabolic process that becomes activated under stress conditions, such as amino acid starvation and cytosolic Ca2+ upload. However, the molecular details on how both conditions control autophagy are still not fully understood. Here we link essential amino acid starvation and Ca2+ in a signaling pathway to activate autophagy. We show that withdrawal of essential amino acids leads to an increase in cytosolic Ca2+, arising from both extracellular medium and intracellular stores, which induces the activation of adenosine monophosphate-activated protein kinase (AMPK) via Ca2+/calmodulin-dependent kinase kinase-beta (CaMKK-beta). Furthermore, we show that autophagy induced by amino acid starvation requires AMPK, as this induction is attenuated in its absence. Subsequently, AMPK activates UNC-51-like kinase (ULK1), a mammalian autophagy-initiating kinase, through phosphorylation at Ser-555 in a process that requires CaMKK-beta. Finally, the mammalian target of rapamycin complex C1 (mTORC1), a negative regulator of autophagy downstream of AMPK, is inhibited by amino acid starvation in a Ca2+-sensitive manner, and CaMKK-beta appears to be important for mTORC1 inactivation, especially in the absence of extracellular Ca2+. All these results highlight that amino acid starvation regulates autophagy in part through an increase in cellular Ca2+ that activates a CaMKK-beta-AMPK pathway and inhibits mTORC1, which results in ULK1 stimulation.
引用
收藏
页码:38625 / 38636
页数:12
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