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Multilayered control of protein turnover by TORC1 and ATG1

ABSTRACT: To study TORC1-Atg1 signaling comprehensively and to identify potential additional foci of crosstalk, we chose a mass spectrometry (MS)-based phosphoproteomics strategy combing global proteomics screens in vivo with targeted analyses using in vitro kinase reactions. We present the currently largest compendium of rapamycin-sensitive phosphorylation events in the yeast Saccharomyces cerevisiae, identify numerous unknown TORC1 and Atg1 downstream phosphorylation events, and characterize hitherto unknown, functionally relevant TORC1 target sites on defined Atg proteins.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Saccharomyces Cerevisiae (baker's Yeast)

SUBMITTER: Joern Dengjel

LAB HEAD: Joern Dengjel

PROVIDER: PXD013271 | Pride | 2019-09-30

REPOSITORIES: Pride

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	20170519_ZH_ATG29_w_wort.raw	Raw
	20170519_ZH_ATG29_wo_wort.raw	Raw
	20170530_ZH_ATG29_w_wort.raw	Raw
	20170530_ZH_ATG29_wo_wort1.raw	Raw
	20170530_ZH_ATG29_wo_wort2.raw	Raw

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Multilayered Control of Protein Turnover by TORC1 and Atg1.

Hu Zehan Z Raucci Serena S Jaquenoud Malika M Hatakeyama Riko R Stumpe Michael M Rohr Rudolf R Reggiori Fulvio F De Virgilio Claudio C Dengjel Jörn J

Cell reports 20190901 13

The 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 ...[more]

PMID: 31553916

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Project description:Autophagy is a conserved intracellular degradation pathway exerting various cytoprotective and homeostatic functions by utilizing de novo double membrane vesicle (autophagosome) formation to target a wide range of cytoplasmic material for vacuolar/lysosomal degradation. The Atg1 kinase is one of its key regulators coordinating a complex signaling program to orchestrate autophagosome formation. Combining in vitro reconstitution and cell based approaches, we demonstrate that Atg1 is activated by lipidated Atg8 (Atg8-PE) stimulating substrate phosphorylation along the growing autophagosomal membrane. Atg1 dependent phosphorylation of Atg13 triggers Atg1 complex dissociation resulting in rapid turnover of Atg1 complex subunits at the pre-autophagosomal structure. Moreover, Atg1 recruitment by Atg8-PE self-regulates Atg8-PE levels in the growing autophagosomal membrane by phosphorylating and inhibiting the Atg8 specific E2 and E3. Taken together, our work uncovers the molecular basis for positive and negative feedback imposed by Atg1, and opposing phosphorylation and dephosphorylation events governing the spatiotemporal regulation of autophagy.

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Transcriptional profiling of fruit flies overexpressing the Atg1 gene

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Project description:As a core Autophagy-related (Atg) protein during yeast autophagy, Atg1 interacts with numerous other proteins, and its kinase activity facilitates to phosphorylate various substrates. How Atg1-interacting partners and substrates synergistically orchestrate autophagy remains to be further dissected. In this study, we conducted a transcriptomic, proteomic and phosphoproteomic profiling of Atg1-dependent molecular landscapes during nitrogen starvation-triggered autophagy.

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Sch9 Is a Major Target of TORC1 in Saccharomyces cerevisiae

Project description:The Target Of Rapamycin (TOR) protein is a Ser/Thr kinase that functions in two distinct multiprotein complexes: TORC1 and TORC2. These conserved complexes regulate many different aspects of cell growth in response to intra- and extracellular cues. Here we report the first bona fide substrate of yeast TORC1: the AGC-kinase Sch9. Six amino acids in the c-terminus of Sch9 are directly phosphorylated by TORC1. Phosphorylation of these residues is lost upon rapamycin-treatment as well as carbon- or nitrogen-starvation and transiently reduced following application of osmotic, oxidative or thermal stress. TORC1-dependent phosphorylation is required for Sch9 activity and replacement of residues phosphorylated by TORC1 with Asp/Glu renders Sch9 activity TORC1-independent. Sch9 is required for TORC1 to properly regulate ribosome biogenesis, translation initiation and entry into G0 phase, but not expression of Gln3-dependent genes. Our results suggest that Sch9 functions analogously to the mammalian TORC1 substrate S6K1 rather than the mTORC2 substrate PKB/Akt. Keywords: time course, cell type.

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Sch9 Is a Major Target of TORC1 in Saccharomyces cerevisiae

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