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2018 ; 38
(10
): ä Nephropedia Template TP
gab.com Text
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AMPK Inhibits ULK1-Dependent Autophagosome Formation and Lysosomal Acidification
via Distinct Mechanisms
#MMPMID29507183
Nwadike C
; Williamson LE
; Gallagher LE
; Guan JL
; Chan EYW
Mol Cell Biol
2018[May]; 38
(10
): ä PMID29507183
show ga
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). The MTORC1 and AMPK signaling pathways converge onto the
ULK1/2 autophagy initiation complex. Here, we show that amino acid starvation
promoted formation of ULK1- and sequestosome 1/p62-positive early autophagosomes.
Autophagosome initiation was controlled by MTORC1 sensing glutamine, leucine, and
arginine levels together. In contrast, glucose starvation promoted AMPK activity,
phosphorylation of ULK1 Ser555, 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. In addition 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.