Abstract
Autophagy is a cellular catabolic process critical for cell viability and homoeostasis. Inhibition of mammalian target of rapamycin (mTOR) complex-1 (mTORC1) activates autophagy. A puzzling observation is that amino acid starvation triggers more rapid autophagy than pharmacological inhibition of mTORC1, although they both block mTORC1 activity with similar kinetics. Here we find that in addition to mTORC1 inactivation, starvation also causes an increase in phosphatase activity towards ULK1, an mTORC1 substrate whose dephosphorylation is required for autophagy induction. We identify the starvation-stimulated phosphatase for ULK1 as the PP2A–B55α complex. Treatment of cells with starvation but not mTORC1 inhibitors triggers dissociation of PP2A from its inhibitor Alpha4. Furthermore, pancreatic ductal adenocarcinoma cells, whose growth depends on high basal autophagy, possess stronger basal phosphatase activity towards ULK1 and require ULK1 for sustained anchorage-independent growth. Taken together, concurrent mTORC1 inactivation and PP2A–B55α stimulation fuel ULK1-dependent autophagy.
Highlights
Autophagy is a cellular catabolic process critical for cell viability and homoeostasis
We find that this phosphatase activity is abnormally high in pancreatic ductal adenocarcinoma cells that require high basal autophagy for viability
Given the central role of mTORC1 in regulating starvation-induced autophagy, it was puzzling to observe that starvation could induce a faster autophagic response compared with pharmacological inhibition of mTORC1
Summary
Autophagy is a cellular catabolic process critical for cell viability and homoeostasis. We find that in addition to mTORC1 inactivation, starvation causes an increase in phosphatase activity towards ULK1, an mTORC1 substrate whose dephosphorylation is required for autophagy induction. We identify the starvation-stimulated phosphatase for ULK1 as the PP2A–B55a complex. ULK1 is essential for autophagy induced by amino acid starvation (referred to as starvation ) and is directly regulated by energy and nutrient-sensing kinases mTORC1 and AMP-activated protein kinase (AMPK)[9,10,11,12,13]. While the kinases regulating ULK1 phosphorylation are well documented, relatively little is known about the phosphatases involved in this process. Starvation triggers the release of PP2A from this latent complex, resulting in rapid dephosphorylation of ULK1 and autophagy induction. We propose that activation of the phosphatase activity towards ULK1 represents a mechanism that allows cancer cells to activate a strong autophagy flux without turning off mTOR activity, achieving optimal growth and survival capability
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