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.