AMPK inhibits ULK1-dependent autophagosome formation and lysosomal acidification via distinct mechanisms

Chinwendu Nwadike, Leon E. Williamson, Laura E. Gallagher, Jun-Lin Guan, Edmond Y.W. Chan

Research output: Contribution to journalArticlepeer-review

35 Citations (Scopus)
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Autophagy maintains metabolism in response to starvation but each nutrient is sensed distinctly. Amino acid deficiency suppresses mechanistic target of rapamycin complex 1 (MTORC1) while glucose deficiency promotes AMP-activated protein kinase (AMPK). MTORC1 and AMPK signalling pathways converge onto the ULK1/2 autophagy initiation complex. Here, we show that amino acid starvation promoted formation of ULK1- and Sequestosome1/p62-positive early autophagosomes. Autophagosome initiation was controlled by MTORC1 sensing glutamine, leucine and arginine levels together. By contrast, glucose starvation promoted AMPK activity, phosphorylation of ULK1 Ser 555 and LC3-II accumulation, but with dynamics consistent with a block in autophagy flux. We studied the flux pathway and found that starvation of amino acid, but not of glucose, activated lysosomal acidification, which occurred independently of autophagy and ULK1. Further to lack of activation, glucose starvation inhibited the ability of amino acid starvation to activate both autophagosome formation and the lysosome. Activation of AMPK and phosphorylation of ULK1 were determined to specifically inhibit autophagosome formation. AMPK activation also was sufficient to prevent lysosome acidification. These results indicate concerted but distinct AMPK-dependent mechanisms to suppress early and late phases of autophagy.
Original languageEnglish
Article numbere00023-18
Number of pages22
JournalMolecular and Cellular Biology
Issue number10
Early online date5 Mar 2018
Publication statusPublished - 31 May 2018


  • autophagy
  • amino acid starvation
  • glucose starvation
  • ULK1
  • MTORC1
  • AMPK
  • leucine
  • glutamine
  • arginine
  • lysosome acidification


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