Summary
The activities of both mTORC1 and mTORC2 are negatively regulated by their endogenous inhibitor, DEPTOR. As such, the abundance of DEPTOR is a critical determinant in the activity status of the mTOR network. DEPTOR stability is governed by the 26S-proteasome through a largely unknown mechanism. Here we describe an mTOR-dependent phosphorylation-driven pathway for DEPTOR destruction via SCFβ-TRCP. DEPTOR phosphorylation by mTOR in response to growth signals, and in collaboration with casein kinase I (CKI), generates a phosphodegron that binds β-TRCP. Failure to degrade DEPTOR through either degron mutation or β-TRCP depletion leads to reduced mTOR activity, reduced S6 kinase activity, and activation of autophagy to reduce cell growth. This work expands the current understanding of mTOR regulation by revealing a positive feedback loop involving mTOR and CKI-dependent turnover of its inhibitor, DEPTOR, suggesting that misregulation of the DEPTOR destruction pathway might contribute to aberrant activation of mTOR in disease.
Increased activity of the mammalian target of rapamycin (mTOR) signalling pathway, a crucial nutrient sensor, enhances ageing and ageing related diseases, including cancer and Dilated Car-diomyopathy (DCM). To further elucidate the physiological role of mTOR, a serine/threonine ki-nase, we devised a novel tractable proteomics strategy which combines interaction proteomics, proximity based proteomics and quantitative phosphoproteomics to identify interactors, including substrates of mTOR. We identified 58 candidate mTOR substrates several of which were further validated. We characterized one of the validated mTOR substrates, LARP1, an RNA binding pro-tein. mTOR-dependent phosphorylation of LARP1 is nutrient sensitive and regulates the RNA-binding ability of LARP1. In addition, we show that mTOR activity, as well as LARP1 and phosphorylated LARP1 levels are elevated in a congenital mouse model of DCM in which the mTOR pathway is activated, revealing a role of LARP1 in the development of DCM.
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