PP2C phosphatases promote autophagy by dephosphorylation of the Atg1 complex

Memisoglu, Gonen; Eapen, Vinay V.; Yang, Ying; Klionsky, Daniel J.; Haber, James E.

doi:10.1073/pnas.1817078116

Cited by 51 publications

(43 citation statements)

References 60 publications

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“…During starvation and cellular stress when mTORC1 is inactive, it dissociates from ULK1 and the phosphorylation of ULK1 and Atg13 at the inhibitory sites is relieved by phosphatases [57,58]. While ULK1 is dephosphorylated by protein phosphatase 2A (PP2A) [57] and protein phosphatase 1D magnesium-dependent delta isoform (PPM1D) [58] Atg13 is dephosphorylated by PP2C phosphatases, Ptc2 and Ptc3 [59]. ULK1 becomes activated by autophosphorylation at Thr180 [60] and phosphorylates Atg13, FIP200 and Atg101 [40,51,61] (Figure 2).…”

Section: Regulation Of Autophagy By Mtorc1mentioning

confidence: 99%

The Emerging Roles of mTORC1 in Macromanaging Autophagy

Dossou

Basu

2019

Cancers

211

127

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Autophagy is a process of self-degradation that enables the cell to survive when faced with starvation or stressful conditions. The mechanistic target of rapamycin (mTOR), also known as the mammalian target of rapamycin, plays a critical role in maintaining a balance between cellular anabolism and catabolism. mTOR complex 1 (mTORC1) was unveiled as a master regulator of autophagy since inhibition of mTORC1 was required to initiate the autophagy process. Evidence has emerged in recent years to indicate that mTORC1 also directly regulates the subsequent steps of the autophagy process, including the nucleation, autophagosome elongation, autophagosome maturation and termination. By phosphorylating select protein targets of the autophagy core machinery and/or their regulators, mTORC1 can alter their functions, increase their proteasomal degradation or modulate their acetylation status, which is a key switch of the autophagy process. Moreover, it phosphorylates and alters the subcellular localization of transcription factors to suppress the expression of genes needed for autophagosome formation and lysosome biogenesis. The purpose of this review article is to critically analyze current literatures to provide an integrated view of how mTORC1 regulates various steps of the autophagy process.

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Section: Regulation Of Autophagy By Mtorc1mentioning

confidence: 99%

The Emerging Roles of mTORC1 in Macromanaging Autophagy

Dossou

Basu

2019

Cancers

211

127

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“…In vitro analyses confirmed the Atg1 motif generated using in vivo data ( Figure 4E). The inferred in vivo and in vitro TORC1 motifs, however, differed substantially, which indicates that many of the rapamycin-sensitive phosphosites might be regulated indirectly by TORC1 effector kinases, such as Sch9 ( Figure 2D), or protein phosphatases, such as Ptc2/3, that remove inhibitory TORC1 phosphosites from the Atg1-Atg13 complex (Memisoglu et al, 2019). From the in vitro data, we conclude that TORC1 phosphorylates preferentially serine residues that are followed Proteins carrying significantly regulated phosphosites were screened for kinases and known members of TORC1 and Atg1 signaling pathways.…”

Section: Torc1 and Atg1 Regulate Autophagy On Multiple Layersmentioning

confidence: 99%

Multilayered Control of Protein Turnover by TORC1 and Atg1

et al. 2019

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Graphical Abstract Highlights d S. cerevisiae proteins harbor a minimum of 45,000 distinct phosphorylation sites d TORC1 and Atg1 regulate at least 26 protein and lipid kinases d Atg1 phosphorylates upstream regulators of TORC1 d TORC1 phosphorylates Atg29 to inhibit autophagy SUMMARYThe target of rapamycin complex 1 (TORC1) is a master regulator of cell homeostasis, which promotes anabolic reactions and synchronously inhibits catabolic processes such as autophagy-mediated protein degradation. Its prime autophagy target is Atg13, a subunit of the Atg1 kinase complex that acts as the gatekeeper of canonical autophagy. To study whether the activities of TORC1 and Atg1 are coupled through additional, more intricate control mechanisms than simply this linear pathway, we analyzed the epistatic relationship between TORC1 and Atg1 by using quantitative phosphoproteomics. Our in vivo data, combined with targeted in vitro TORC1 and Atg1 kinase assays, not only uncover numerous TORC1 and Atg1 effectors, but also suggest distinct bi-directional regulatory feedback loops and characterize Atg29 as a commonly regulated downstream target of both TORC1 and Atg1. Thus, an exquisitely multilayered regulatory network appears to coordinate TORC1 and Atg1 activities to robustly tune autophagy in response to nutritional cues.

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“…In addition, autophagy plays roles in abiotic stress responses including oxidative stress, drought, and salt [12]. Two PP2Cs were reported to promote macroautophagy by dephosphorylating Atg1 complex [13]. Besides, tremendous transcription factors (like MYB, WRKY, NAC, and so on) play vital roles in regulating plant response to abiotic stress [14,15].…”

Section: Introductionmentioning

confidence: 99%

The Maize Clade A PP2C Phosphatases Play Critical Roles in Multiple Abiotic Stress Responses

Sun

et al. 2019

IJMS

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As the core components of abscisic acid (ABA) signal pathway, Clade A PP2C (PP2C-A) phosphatases in ABA-dependent stress responses have been well studied in Arabidopsis. However, the roles and natural variations of maize PP2C-A in stress responses remain largely unknown. In this study, we investigated the expression patterns of ZmPP2C-As treated with multiple stresses and generated transgenic Arabidopsis plants overexpressing most of the ZmPP2C-A genes. The results showed that the expression of most ZmPP2C-As were dramatically induced by multiple stresses (drought, salt, and ABA), indicating that these genes may have important roles in response to these stresses. Compared with wild-type plants, ZmPP2C-A1, ZmPP2C-A2, and ZmPP2C-A6 overexpression plants had higher germination rates after ABA and NaCl treatments. ZmPP2C-A2 and ZmPP2C-A6 negatively regulated drought responses as the plants overexpressing these genes had lower survival rates, higher leaf water loss rates, and lower proline accumulation compared to wild type plants. The natural variations of ZmPP2C-As associated with drought tolerance were also analyzed and favorable alleles were detected. We widely studied the roles of ZmPP2C-A genes in stress responses and the natural variations detected in these genes have the potential to be used as molecular markers in genetic improvement of maize drought tolerance.

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PP2C phosphatases promote autophagy by dephosphorylation of the Atg1 complex

Cited by 51 publications

References 60 publications

The Emerging Roles of mTORC1 in Macromanaging Autophagy

The Emerging Roles of mTORC1 in Macromanaging Autophagy

Multilayered Control of Protein Turnover by TORC1 and Atg1

The Maize Clade A PP2C Phosphatases Play Critical Roles in Multiple Abiotic Stress Responses

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