Phosphoproteomic responses of TORC1 target kinases reveal discrete and convergent mechanisms that orchestrate the quiescence program in yeast.

Ladislav Dokládal,Michael Stumpe,Jörn Dengjel,Claudio De Virgilio,Zehan Hu,Malika Jaquenoud

doi:10.1016/j.celrep.2021.110149

Ladislav Dokládal, Michael Stumpe + Show 4 more

Open Access

https://doi.org/10.1016/j.celrep.2021.110149

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Journal: Cell Reports	Publication Date: Dec 1, 2021
Citations: 25	License type: cc-by

Affiliation: University of Fribourg

Abstract

The eukaryotic TORC1 kinase assimilates diverse environmental cues, including growth factors and nutrients, to control growth by tuning anabolic and catabolic processes. In yeast, TORC1 stimulates protein synthesis in response to abundant nutrients primarily through its proximal effector kinase Sch9. Conversely, TORC1 inhibition following nutrient limitation unlocks various distally controlled kinases (e.g., Atg1, Gcn2, Npr1, Rim15, Slt2/Mpk1, and Yak1), which cooperate through poorly defined circuits to orchestrate the quiescence program. To better define the signaling landscape of the latter kinases, we use invivo quantitative phosphoproteomics. Through pinpointing known and uncharted Npr1, Rim15, Slt2/Mpk1, and Yak1 effectors, our study examines the architecture of the distally controlled TORC1 kinase network. Accordingly, this is built on a combination of discrete, convergent, and multilayered feedback regulatory mechanisms, which likely ensure homeostatic control of and/or robust responses by TORC1 and its effector kinases under fluctuating nutritional conditions.

Highlights

The target of the rapamycin complex 1 (TORC1) pathway pivotally regulates eukaryotic cell growth and couples diverse environmental signals, including growth factors, hormones, and nutrients, to downstream effectors to control anabolic and catabolic processes in a reciprocal manner (Gonzalez and Hall, 2017; Sarbassov et al, 2005)
Deregulation of mammalian TORC1 in humans is associated with pathologies including cancer, obesity, type 2 diabetes, and neurodegeneration (Cornu et al, 2013; Liu and Sabatini, 2020), which emphasizes its central role in growth control
Nutrient limitation or rapamycin treatment attenuate signaling through TORC1, which drives cells into a quiescent state that is characterized by a distinct array of physiological, biochemical, and morphological traits (De Virgilio, 2012; Zaragoza et al, 1998)

Summary

SUMMARY

The eukaryotic TORC1 kinase assimilates diverse environmental cues, including growth factors and nutrients, to control growth by tuning anabolic and catabolic processes. TORC1 stimulates protein synthesis in response to abundant nutrients primarily through its proximal effector kinase Sch. TORC1 inhibition following nutrient limitation unlocks various distally controlled kinases (e.g., Atg, Gcn, Npr, Rim, Slt2/Mpk, and Yak1), which cooperate through poorly defined circuits to orchestrate the quiescence program. Through pinpointing known and uncharted Npr, Rim, Slt2/Mpk, and Yak effectors, our study examines the architecture of the distally controlled TORC1 kinase network. This is built on a combination of discrete, convergent, and multilayered feedback regulatory mechanisms, which likely ensure homeostatic control of and/or robust responses by TORC1 and its effector kinases under fluctuating nutritional conditions

INTRODUCTION

RESULTS AND DISCUSSION

METHOD DETAILS