Biology subjects

Lamprakis, A.

Publications and source records attributed to Lamprakis, A..

2 recordsLinked to original sources

bioRxiv2026

TSC1 phosphorylation by lysosomal mTORC1 establishes a minimal autoregulatory feedback loop

mTORC1 lies at the center of an intricate signaling network that allows cells to homeostatically respond to a multitude of intra- and extracellular cues. Although this network is dynamically rewired to prevent excessive mTORC1 activation under permissive conditions, the mechanisms that fine-tune its activity remain incompletely understood. Here, we identify TSC1 (tuberous sclerosis complex 1), a core subunit of the mTORC1-inhibitory TSC complex, as a direct mTORC1 substrate, thus establishing an autoregulatory circuit in mTOR signaling. Notably, TSC1 combines features of both canonical and non-canonical/lysosomal mTORC1 substrates: while its phosphorylation depends on Rheb activation and growth factor signaling, it also requires an intact lysosomal LAMTOR-Rag GTPase supercomplex. In turn, TSC1 phosphorylation selectively influences lysosomal mTORC1 signaling, as expression of a phospho-dead TSC1 mutant is associated with lower levels of TFEB phosphorylation, increased nuclear TFE3 translocation, and enhanced lysosome biogenesis, while phosphorylation of S6K1, a non-lysosomal canonical substrate, remains largely unaffected. Mechanistically, phosphorylation of TSC1 by mTORC1 promotes its stability, with a non-phosphorylatable mutant undergoing proteasomal degradation. In sum, these findings reveal a minimal feedback loop within the mTOR network that orchestrates compartmentalized signaling to selectively control the activation of processes downstream of lysosomal mTORC1 signaling.

cell biology↗

bioRxiv2022

Malonyl-CoA is an ancient physiological ATP-competitive mTORC1 inhibitor

Cell growth is regulated primarily by the mammalian/mechanistic Target of Rapamycin Complex 1 (mTORC1) that functions both as a nutrient sensor and a master controller of virtually all biosynthetic pathways 1. This ensures that cells are metabolically active only when conditions are optimal for growth. Notably, although mTORC1 is known to regulate fatty acid (FA) biosynthesis, how and whether the cellular lipid biosynthetic capacity signals back to fine-tune mTORC1 activity remains poorly understood. Here, we show that mTORC1 senses the capacity of a cell to synthesize FAs by detecting the levels of malonyl-CoA, an intermediate of this biosynthetic pathway. We find that, in both yeast and mammalian cells, this regulation is very direct, with malonyl-CoA binding to the mTOR catalytic pocket and acting as a specific ATP-competitive inhibitor. When ACC1 (acetyl-CoA carboxylase 1) is hyperactive or FASN (fatty acid synthase) is downregulated/inhibited, elevated malonyl-CoA levels are channelled to proximal mTOR molecules that form direct protein-protein interactions with ACC1 and FASN. Our findings represent a conserved, unique, homeostatic mechanism whereby impaired FA biogenesis leads to reduced mTORC1 activity to coordinatively link this metabolic pathway to the overall cellular biosynthetic output. Moreover, they reveal the first-described example of a physiological metabolite that directly inhibits the activity of a signalling kinase by competing with ATP for binding.

cell biology↗