Abstract
Autophagy is an evolutionarily conserved process that degrades cellular components to restore energy homeostasis under limited nutrient conditions. How this starvation-induced autophagy is regulated at the whole-body level is not fully understood. Here, we show that the tumor suppressor Lkb1, which activates the key energy sensor AMPK, also regulates starvation-induced autophagy at the organismal level. Lkb1-deficient zebrafish larvae fail to activate autophagy in response to nutrient restriction upon yolk termination, shown by reduced levels of the autophagy-activating proteins Atg5, Lc3-II and Becn1, and aberrant accumulation of the cargo receptor and autophagy substrate p62. We demonstrate that the autophagy defect in lkb1 mutants can be partially rescued by inhibiting mTOR signaling but not by inhibiting the PI3K pathway. Interestingly, mTOR-independent activation of autophagy restores degradation of the aberrantly accumulated p62 in lkb1 mutants and prolongs their survival. Our data uncover a novel critical role for Lkb1 in regulating starvation-induced autophagy at the organismal level, providing mechanistic insight into metabolic adaptation during development.
Highlights
Autophagy is a highly conserved, multi-step intracellular process of self-degradation
The LKB1/AMPK axis is a negative regulator of mechanistic target of rapamycin (mTOR) signaling[8] and mTOR signaling is a known inhibitor of autophagy[17]
To determine whether mTOR signaling mediates the inhibition of autophagy seen in the lkb[1] mutants at 6 dpf, we examined whether rapamycin treatment could restore autophagy in these mutants
Summary
Organisms adapt their metabolism in response to nutrient limitation to restore energy homeostasis and ensure survival. Occurred even while the yolk is not yet consumed, suggesting that even though the larvae do not show a morphological phenotype at this embryonic stage, the loss of Lkb[1] appears to sensitize them to additional stress This stress may be autophagy inhibition, or related to alternative mechanisms, as autophagy-independent functions have been reported for several of the autophagy-related genes[57, 58], including Atg[559]. While the mTOR-inhibitor rapamycin increased Lc3-II accumulation in lkb[1] larvae, autophagy was not completely restored since p62 still accumulated This may be due to the high mTOR activity in the mutants that could not be fully blocked by rapamycin treatment under these experimental conditions. Inhibition of the PI3K pathway activated autophagy in wt larvae, but not in lkb[1] mutants, and did not prolong their survival. Since defects in autophagy are implicated in a plethora of diseases, a better understanding of the upstream regulatory pathways could provide new insights into their pathophysiology
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