Tor Directly Controls the Atg1 Kinase Complex To Regulate Autophagy

Kamada, Yoshiaki; Yoshino, Ken‐ichi; Kondo, Chika; Kawamata, Tomoko; Oshiro, Noriko; Yonezawa, Kazuyoshi; Ohsumi, Yoshinori

doi:10.1128/mcb.01344-09

Cited by 440 publications

(438 citation statements)

References 49 publications

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“…Atg13 is required for Atg1 kinase activity. Atg13 is hyperphosphorylated under nutrient-rich conditions, and its phosphorylation is regulated by TOR complex 1 (TORC1) [69] and/or PKA [70]. Atg13 is rapidly, but only partially, dephosphorylated upon autophagy induction [71].…”

Section: Yeast Atg1 Kinase Complexmentioning

confidence: 99%

The machinery of macroautophagy

et al. 2013

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Autophagy is a primarily degradative pathway that takes place in all eukaryotic cells. It is used for recycling cytoplasm to generate macromolecular building blocks and energy under stress conditions, to remove superfluous and damaged organelles to adapt to changing nutrient conditions and to maintain cellular homeostasis. In addition, autophagy plays a critical role in cytoprotection by preventing the accumulation of toxic proteins and through its action in various aspects of immunity including the elimination of invasive microbes and its participation in antigen presentation. The most prevalent form of autophagy is macroautophagy, and during this process, the cell forms a double-membrane sequestering compartment termed the phagophore, which matures into an autophagosome. Following delivery to the vacuole or lysosome, the cargo is degraded and the resulting macromolecules are released back into the cytosol for reuse. The past two decades have resulted in a tremendous increase with regard to the molecular studies of autophagy being carried out in yeast and other eukaryotes. Part of the surge in interest in this topic is due to the connection of autophagy with a wide range of human pathophysiologies including cancer, myopathies, diabetes and neurodegenerative disease. However, there are still many aspects of autophagy that remain unclear, including the process of phagophore formation, the regulatory mechanisms that control its induction and the function of most of the autophagy-related proteins. In this review, we focus on macroautophagy, briefly describing the discovery of this process in mammalian cells, discussing the current views concerning the donor membrane that forms the phagophore, and characterizing the autophagy machinery including the available structural information.

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Section: Yeast Atg1 Kinase Complexmentioning

confidence: 99%

The machinery of macroautophagy

et al. 2013

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“…Transcriptional, post-transcriptional and post-translational regulation are all used to modulate autophagy in order to adapt to different types of environmental stress, [7][8][9] and several Atg proteins are phosphorylated. [10][11][12][13][14] Atg9, conserved from yeast to mammals, is the only transmembrane protein identified in the yeast autophagy core machinery. 15 One of the unique features of Atg9 concerns its subcellular distribution.…”

Section: Introductionmentioning

confidence: 99%

Phosphorylation of Atg9 regulates movement to the phagophore assembly site and the rate of autophagosome formation

Feng¹,

Backues²,

Baba³

et al. 2016

Autophagy

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Macroautophagy is primarily a degradative process that cells use to break down their own components to recycle macromolecules and provide energy under stress conditions, and defects in macroautophagy lead to a wide range of diseases. Atg9, conserved from yeast to mammals, is the only identified transmembrane protein in the yeast core macroautophagy machinery required for formation of the sequestering compartment termed the autophagosome. This protein undergoes dynamic movement between the phagophore assembly site (PAS), where the autophagosome precursor is nucleated, and peripheral sites that may provide donor membrane for expansion of the phagophore. Atg9 is a phosphoprotein that is regulated by the Atg1 kinase. We used stable isotope labeling by amino acids in cell culture (SILAC) to identify phosphorylation sites on this protein and identified an Atg1-independent phosphorylation site at serine 122. A nonphosphorylatable Atg9 mutant showed decreased autophagy activity, whereas the phosphomimetic mutant enhanced activity. Electron microscopy analysis suggests that the different levels of autophagy activity reflect differences in autophagosome formation, correlating with the delivery of Atg9 to the PAS. Finally, this phosphorylation regulates Atg9 interaction with Atg23 and Atg27.

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“…Under nutrient-rich conditions the MTOR complex phosphorylates the ULK1 and ATG13 proteins, leading to disruption of the ULK complex and inhibition of autophagy initiation. [7][8][9] Structural analysis revealed dephosphorylation of specific serine residues in the Atg13 protein that may enhance its interaction with Atg1 and Atg17 in yeasts, whereas in mammals ULK1 constitutively forms a complex with ATG13 irrespective of nutrient conditions. 10 A key energy sensor, AMP-activated protein kinase (AMPK), directly regulates autophagic activity through phosphorylation of ULK1.…”

Section: Introductionmentioning

confidence: 99%

Suppressed translation and ULK1 degradation as potential mechanisms of autophagy limitation under prolonged starvation

Allavena

Boyd

et al. 2016

Autophagy

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Macroautophagy/autophagy is a well-organized process of intracellular degradation, which is rapidly activated under starvation conditions. Recent data demonstrate a transcriptional upregulation of several autophagy genes as a mechanism that controls autophagy in response to starvation. Here we report that despite the significant upregulation of mRNA of the essential autophagy initiation gene ULK1, its protein level is rapidly reduced under starvation. Although both autophagic and proteasomal systems contribute to the degradation of ULK1, under prolonged nitrogen deprivation, its level was still reduced in ATG7 knockout cells, and only initially stabilized in cells treated with the lysosomal or proteasomal inhibitors. We demonstrate that under starvation, protein translation is rapidly diminished and, similar to treatments with the proteosynthesis inhibitors cycloheximide or anisomycin, is associated with a significant reduction of ULK1. Furthermore, it was found that inhibition of the mitochondrial respiratory complexes or the mitochondrial ATP synthase function that could also take place in the absence of substrates, promote upregulation of ULK1 mRNA and protein expression in an AMPK-dependent manner in U1810 lung cancer cells growing in complete culture medium. These inhibitors could also drastically increase the ULK1 protein in U1810 cells with knockout of ATG13, where the ULK1 expression is significantly diminished. However, such upregulation of ULK1 protein is negligible under starvation conditions, further signifying the contribution of translation and suggesting that transcriptional upregulation of ULK1 protein will be diminished under such conditions. Thus, we propose a model where inhibition of protein translation, together with the degradation systems, limit autophagy during starvation.

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Tor Directly Controls the Atg1 Kinase Complex To Regulate Autophagy

Cited by 440 publications

References 49 publications

The machinery of macroautophagy

The machinery of macroautophagy

Phosphorylation of Atg9 regulates movement to the phagophore assembly site and the rate of autophagosome formation

Suppressed translation and ULK1 degradation as potential mechanisms of autophagy limitation under prolonged starvation

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