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

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 preliminary data show that core SG proteins bind mTOR at steady-state and suggest that they are key controllers of mTOR. In BEYOND STRESS, we will 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 bio-logical studies, we will identify and functionally 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.