Nutrient starvation elicits an acute autophagic response mediated by Ulk1 dephosphorylation and its subsequent dissociation from AMPK

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.

Hexokinase II integrates energy metabolism and cellular protection: Akting on mitochondria and TORCing to autophagy

“…40,59,154 mTORC1 phosphorylates and inhibits the autophagy-activating kinase ULK1. 155,156 Upon nutrient deprivation, the activity of mTORC1 is suppressed and AMPK is activated. Consequently, ULK1 is activated and initiates membrane nucleation, which is followed by sequestration and degradation.…”

“…Consequently, ULK1 is activated and initiates membrane nucleation, which is followed by sequestration and degradation. [155][156][157][158][159][160] Although it has been widely accepted that autophagy is induced in response to metabolic suppression, the molecular links between metabolic and autophagic pathways have not been fully elucidated. Recently, we made the surprising discovery that HK-II facilitates autophagy in response to glucose deprivation to protect cells 117 (Figure 4).…”

mTOR-Dependent Cell Survival Mechanisms

“…In nutrient-rich conditions, mTORC1 associates with the ULK1 -mAtg13 -FIP200 complex through a direct interaction between RAPTOR and ULK1, and this facilitates phosphorylation of both mAtg13 and ULK1 by mTORC1. The function of mTORC1-dependent ULK1 phosphorylation is not entirely clear, but it appears to diminish ULK1 kinase activity, thus reducing autophagic vesicle formation Shang et al 2011). …”

Heat shock response and autophagy—cooperation and control

“…[60][61][62] Moreover, direct physical interaction between AMPK or MTOR and ULK1 (unc-51 like autophagy activating kinase 1) plays a crucial role in the regulation of mammalian autophagy. [63][64][65][66][67][68][69] Under conditions of nutrients abundance, the activated MTOR phosphorylates ULK1 and prevents its interaction with AMPK. Conversely, under starvation conditions, AMPK-induced MTOR inhibition prevents MTOR from binding to ULK1.…”