Withdrawal of essential amino acids increases autophagy by a pathway involving Ca2+/calmodulin-dependent kinase kinase-ß (CaMKK-ß).
J Biol Chem
; 287(46): 38625-36, 2012 Nov 09.
Article
em En
| MEDLINE
| ID: mdl-23027865
ABSTRACT
Autophagy is the main lysosomal catabolic process that becomes activated under stress conditions, such as amino acid starvation and cytosolic Ca(2+) upload. However, the molecular details on how both conditions control autophagy are still not fully understood. Here we link essential amino acid starvation and Ca(2+) in a signaling pathway to activate autophagy. We show that withdrawal of essential amino acids leads to an increase in cytosolic Ca(2+), arising from both extracellular medium and intracellular stores, which induces the activation of adenosine monophosphate-activated protein kinase (AMPK) via Ca(2+)/calmodulin-dependent kinase kinase-ß (CaMKK-ß). 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-ß. 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 Ca(2+)-sensitive manner, and CaMKK-ß appears to be important for mTORC1 inactivation, especially in the absence of extracellular Ca(2+). All these results highlight that amino acid starvation regulates autophagy in part through an increase in cellular Ca(2+) that activates a CaMKK-ß-AMPK pathway and inhibits mTORC1, which results in ULK1 stimulation.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Complexos Multiproteicos
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Quinase da Proteína Quinase Dependente de Cálcio-Calmodulina
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Serina-Treonina Quinases TOR
Limite:
Animals
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Humans
Idioma:
En
Ano de publicação:
2012
Tipo de documento:
Article