Nutrient starvation elicits an acute autophagic response mediated by Ulk1 dephosphorylation and its subsequent dissociation from AMPK. Proc Natl Acad Sci USA

Howard Hughes Medical Institute and Department of Biochemistry, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 03/2011; 108(12):4788-93. DOI: 10.1073/pnas.1100844108
Source: PubMed

ABSTRACT Macroautophagy (herein referred to as autophagy) is an evolutionarily conserved self-digestive process cells adapt to starvation and other stress responses. Upon starvation, autophagy is induced, providing cells with needed nutrient supplies. We report here that Unc-51-like kinase 1 (Ulk1), a key initiator for mammalian autophagy, undergoes dramatic dephosphorylation upon starvation, particularly at serine 638 and serine 758. Phosphorylations of Ulk1 are mediated by mammalian target-of-rapamycin (mTOR) kinase and adenosine monophosphate activated protein kinase (AMPK). AMPK interacts with Ulk1 in a nutrient-dependent manner. Proper phosphorylations on Ulk1 are crucial for Ulk1/AMPK association, as a single serine-to-alanine mutation (S758A) at Ulk1 impairs this interaction. Compared to the wild-type ULK1, this Ulk1-S758A mutant initiates starvation-induced autophagy faster at an early time point, but does not alter the maximum capacity of autophagy when starvation prolongs. This study therefore revealed previously unnoticed acute autophagy response to environmental changes.

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Available from: Fenghe Du, Aug 21, 2015
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    • "Mirroring these findings, phosphorylation at Ser2481 of mTOR, implicated to be an autophosphorylation site and indicative of TORC1 activity (Soliman et al., 2010), displays parallel changes to those in its substrates (data not shown). ULK-1, a positive regulator of autophagy, has been demonstrated to be inhibited when phosphorylated at Ser757/758 by mTOR (Kim et al., 2011; Shang et al., 2011). We also demonstrated that phosphorylation of Ser757 in ULK-1 is reduced by glucose deprivation in cardiomyocytes and decreased further by WT HK-II overexpression. "
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    ABSTRACT: Hexokinase-II (HK-II) catalyzes the first step of glycolysis and also functions as a protective molecule; however, its role in protective autophagy has not been determined. Results showed that inhibition of HK-II diminished, while overexpression of HK-II potentiated, autophagy induced by glucose deprivation in cardiomyocyte and noncardiomyocyte cells. Immunoprecipitation studies revealed that HK-II binds to and inhibits the autophagy suppressor, mTOR complex 1 (TORC1), and that this binding was increased by glucose deprivation. The TOS motif, a scaffold sequence responsible for binding TORC1 substrates, is present in HK-II, and mutating it blocked its ability to bind to TORC1 and regulate protective autophagy. The transition from glycolysis to autophagy appears to be regulated by a decrease in glucose-6 phosphate. We suggest that HK-II binds TORC1 as a decoy substrate and provides a previously unrecognized mechanism for switching cells from a metabolic economy, based on plentiful energy, to one of conservation, under starvation.
    Molecular cell 01/2014; 53(4). DOI:10.1016/j.molcel.2013.12.019 · 14.46 Impact Factor
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    • "Autophagy is a highly conserved evolutionary process that destroys cellular components producing ATP and macromolecules derived from the destroyed components. Stimuli such as hypoxia [21], infections caused by viruses and bacteria [22], oxidative stress [23], starvation [24] and DNA damage [25] are responsible for triggering autophagy. Both autophagy and the proteasome system are able to degrade proteins, but only autophagy is capable of degrading entire organelles. "
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    • "During periods of starvation, the stimulation of autophagy is crucial to provide cells with the amino acids necessary to maintain metabolism and the ATP levels compatible with survival. Nutrient-sensitive autophagy is a highly regulated process, mainly by mTOR and AMPK in mammals [3]. However, autophagy also occurs constitutively in basal conditions in order to maintain homeostasis. "
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    ABSTRACT: DOR is a bi-functional protein that regulates transcription and enhances starvation-induced autophagy. While autophagy has been mostly described as a stress-response mechanism, cells also need autophagy to maintain homeostasis in basal conditions. However, the mechanisms regulating basal autophagy still remain unknown. Our results show that DOR acts in basal autophagy. Indeed, DOR already undergoes nucleo-cytoplasmic shuttling in basal conditions and, surprisingly, DOR exits continuously the nucleus and traverses the nucleolus. However, the nucleolus integrity is not essential for both DOR nucleo-cytoplasmic shuttling and DOR function on basal autophagy. Taken together, we propose that DOR exit from the nucleus is essential for basal autophagy stimulation even under nucleolus disruption.
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