Regulation of mATG9 trafficking by Src- and ULK1-mediated phosphorylation in basal and starvation-induced autophagy

Accumulating evidence has indicated a role for autophagy-related (Atgs) proteins in cell regulation which is independent of their autophagic activities. As the only known transmembrane protein essential for autophagy, Atg9 cycles between the trans-Golgi network (TGN) and endosomes. Here, we report a function for mammalian Atg9 (mAtg9) in the transport of lysosomal hydrolases which impacts the lysosomal degradation capacity. Depletion of mAtg9 inhibits the degradation of epidermal growth factor receptor and the maturation of cathepsin D and cathepsin L. mAtg9 interacts with adaptor protein-1 (AP1) and the cation-independent mannose-6-phosphate receptor, facilitating AP1 polymerization and the transport of cathepsin D from the TGN. These results suggest that mAtg9 may serve as a coreceptor of lysosomal hydrolases for their TGN export by cycling between the TGN and endosomes.

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“…D). To further confirm these observations, we used another mAtg9 shRNA and ATG9A KO cells , and consistent results were obtained (Fig. S2A–F).…”

Section: Resultssupporting

confidence: 72%

Mammalian Atg9 contributes to the post‐Golgi transport of lysosomal hydrolases by interacting with adaptor protein‐1

et al. 2017

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“…162), the downstream effectors ATG9 (REF. 163), ATG14L 159 , VPS34 (also known as PI3K type 3), Beclin1 and AMBRA1 (REFS 161,164), and the trafficking protein Sec16A 165 (BOX 2, FIG. 4 and reviewed in REF.…”

Section: Ampk Regulates Autophagy and Mitophagymentioning

confidence: 99%

AMPK: guardian of metabolism and mitochondrial homeostasis

Herzig

Shaw

2017

Nat Rev Mol Cell Biol

2,424

2,008

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Cells constantly adapt their metabolism to meet their energy needs and respond to nutrient availability. Eukaryotes have evolved a very sophisticated system to sense low cellular ATP levels via the serine/threonine kinase AMP-activated protein kinase (AMPK) complex. Under conditions of low energy, AMPK phosphorylates specific enzymes and growth control nodes to increase ATP generation and decrease ATP consumption. In the past decade, the discovery of numerous new AMPK substrates has led to a more complete understanding of the minimal number of steps required to reprogramme cellular metabolism from anabolism to catabolism. This energy switch controls cell growth and several other cellular processes, including lipid and glucose metabolism and autophagy. Recent studies have revealed that one ancestral function of AMPK is to promote mitochondrial health, and multiple newly discovered targets of AMPK are involved in various aspects of mitochondrial homeostasis, including mitophagy This Review discusses how AMPK functions as a central mediator of the cellular response to energetic stress and mitochondrial insults and coordinates multiple features of autophagy and mitochondrial biology.

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“…Given that both AMPK and ULK1 have been reported to directly phosphorylate distinct sites in both Beclin-1 and Vps34, much remains to be clarified about the temporal and spatial control of autophagy initiation in response to different stresses. In addition, AMPK and ULK1 have also both been reported to phosphorylate and control the localization of Atg9, a transmembrane protein involved in early autophagosome formation (Mack et al, 2012; Weerasekara et al, 2014; Zhou et al, 2017). …”

Section: Metabolic Consequences Of Ampk Activationmentioning

confidence: 99%

AMPK: Mechanisms of Cellular Energy Sensing and Restoration of Metabolic Balance

2017

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AMPK is a highly conserved master regulator of metabolism, which restores energy balance during metabolic stress both at the cellular and physiological levels. The identification of numerous AMPK targets has helped explain how AMPK restores energy homeostasis. Recent advancements, however, demonstrate that regulation of AMPK is also affected by novel contexts, such as subcellular localization and phosphorylation by non-canonical upstream kinases. Notably, the therapeutic potential of AMPK is widely recognized and heavily pursued for treatment of metabolic diseases such as diabetes, but also obesity, inflammation and cancer. Moreover, the recently solved crystal structure of AMPK has shed light both into how nucleotides activate AMPK but, importantly, also into the sites bound by small molecule activators, thus providing a path for improved drugs.

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Regulation of mATG9 trafficking by Src- and ULK1-mediated phosphorylation in basal and starvation-induced autophagy

Cited by 154 publications

References 48 publications

Mammalian Atg9 contributes to the post‐Golgi transport of lysosomal hydrolases by interacting with adaptor protein‐1

Mammalian Atg9 contributes to the post‐Golgi transport of lysosomal hydrolases by interacting with adaptor protein‐1

AMPK: guardian of metabolism and mitochondrial homeostasis

AMPK: Mechanisms of Cellular Energy Sensing and Restoration of Metabolic Balance

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