The stress granule machinery controls metabolic signalling through mTOR at steady-state

Projektinformationen

BEYOND STRESS

ID Finanzhilfevereinbarung: 101054429

DOI

10.3030/101054429

EK-Unterschriftsdatum 31 Mai 2022

Startdatum 1 Mai 2023

Enddatum 30 April 2028

Finanziert unter

• European Research Council (ERC)

Gesamtkosten

€ 2 220 750,00

EU-Beitrag

€ 2 220 750,00

Koordiniert durch

UNIVERSITAETSKLINIKUM ESSEN
Germany

Periodic Reporting for period 1 - BEYOND STRESS (The stress granule machinery controls metabolic signalling through mTOR at steady-state)

Berichtszeitraum: 2023-05-01 bis 2025-10-31

Zusammenfassung vom Kontext und den Gesamtzielen des Projekts

mTOR kinase is an oncogenic master regulator of metabolism and cell growth and is known to reside in two multiprotein complexes. Upon stress, mTOR is inhibited by stress granules (SGs), which recruit mRNAs and signaling factors to promote survival. Current work largely addresses the functions of SG proteins under stress, focusing on their RNA binding properties and SG assembly. However, non-stress functions are emerging. I propose that SG proteins have prime functions in mTOR signaling at metabolic steady-state, in the absence of SGs. Our data show that core SG proteins bind mTOR at steady-state and suggest that they are key controllers of mTOR.
In BEYOND STRESS, we investigate SG proteins as a novel class of mTOR regulators at steady state.
By means of deep proteomics, proteo-metabo-flux, RNASeq, systems modelling, mechanistic and cell biological studies, we identify and characterize the SG interactome of the mTOR complexes. We will delineate the steady-state inputs that signal through SG proteins to mTOR, and we will unravel the mechanistic interplay through which SG assembly impinges on metabolic signaling upon stress. As levels of core SG proteins correlate with cancer outcome, we will explore their linkage with metabolic signaling, prognosis and drug response in breast cancer.
BEYOND STRESS is ground-breaking as
(i) it links SG protein research in stress to steady state mTOR signaling;
(ii) a unifying paradigm of mTOR regulation at steady-state and stress will open new horizons for research on metabolic signaling; and
(iii) SG proteins are emerging as markers and targets for oncogenic signaling through mTOR.
While focusing on mTOR and breast cancer, BEYOND STRESS will likely translate to further networks and
tumor entities, opening new avenues to signaling and cancer research.

Arbeit, die ab Beginn des Projekts bis zum Ende des durch den Bericht erfassten Berichtszeitraums geleistet wurde, und die wichtigsten bis dahin erzielten Ergebnisse

The laboratory moved to a new host institution, new personnel was hired, and laboratory rooms were equipped. Funding for new state-of-the-art mass spectrometers was successfully acquired. The new team members built the technological basis for the planned analyses. Work into the role of novel interactors was initiated and the respective cell biological and biochemical methods established.

Fortschritte, die über den aktuellen Stand der Technik hinausgehen und voraussichtliche potenzielle Auswirkungen (einschließlich der bis dato erzielten sozioökonomischen Auswirkungen und weiter gefassten gesellschaftlichen Auswirkungen des Projekts)

During the reporting period we laid the groundwork to establish SG proteins as components of the mTOR signaling network that sense and convey critical metabolic input to tune adequate cellular responses. While generally advancing the field of mTOR and SG research, these results are expected to be relevant in diverse cancer types for both prognosis and therapy response.