A lysosome-to-nucleus signalling mechanism senses and regulates the lysosome via mTOR and TFEB

By C. Settembre, Roberto Zoncu, Diego L. Medina, F. Vetrini, Serkan Erdin, S. Erdin, Tuong Huynh, Mathieu Ferron, G. Karsenty, M. Vellard and 3 more. EMBO Journal, 2012

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The lysosome plays a key role in cellular homeostasis by controlling both cellular clearance and energy production to respond to environmental cues. However, the mechanisms mediating lysosomal adaptation are largely unknown. Here, we show that the Transcription Factor EB (TFEB), a master regulator of lysosomal biogenesis, colocalizes with master growth regulator mTOR complex 1 (mTORC1) on the lysosomal membrane. When nutrients are present, phosphorylation of TFEB by mTORC1 inhibits TFEB activity. Conversely, pharmacological inhibition of mTORC1, as well as starvation and lysosomal disruption, activates TFEB by promoting its nuclear translocation. In addition, the transcriptional response of lysosomal and autophagic genes to either lysosomal dysfunction or pharmacological inhibition of mTORC1 is suppressed in TFEB−/− cells. Interestingly, the Rag GTPase complex, which senses lysosomal amino acids and activates mTORC1, is both necessary and sufficient to regulate starvation‐ and stress‐induced nuclear translocation of TFEB. These data indicate that the lysosome senses its content and regulates its own biogenesis by a lysosome‐to‐nucleus signalling mechanism that involves TFEB and mTOR.

Subfields: Epidemiology, Molecular Biology, Physiology

View Paper: https://www.semanticscholar.org/paper/aff69c298154a6606280b9806ab9a1cf5a5e8ca7

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Citations in the corpus

Lysosomes as a therapeutic target (2019, background): “The discovery of a stress induced lysosome tonucleus signalling mech anism through TFEB further supports the key role of lysosomes in cellular signalling 36 .”
mTOR Signaling in Growth, Metabolism, and Disease. (2017, background): “mTORC1 also regulates autophagy in part by phosphorylating and inhibiting the nuclear translocation of the transcription factor TFEB, which drives the expression of genes for lysosomal biogenesis and the autophagy machinery (Martina et al., 2012; Roçzniak-Ferguson et al., 2012; Settembre et al., 201”
TFEB-mediated autophagy rescues midbrain dopamine neurons from α-synuclein toxicity (2013, background): “In line with previous studies (38, 39), mTOR inhibition may alleviate the repression of TFEB and facilitate its shuttling”
Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition) (2012, neutral): “nucleus signaling mechanism transcriptionally regulates autophagy and lysosomal biogenesis via MTOR and TFEB.(638) A”
mTOR signaling in growth control and disease (2012, neutral): “lysosomes through the transcription factor EB (TFEB), a basic helix-loop-helix leucine zipper transcription factor that controls many genes with key roles in lysosomal function (Settembre et al., 2012).”
mTOR Signaling in Growth, Metabolism, and Disease (2017, background): “mTORC1 also regulates autophagy in part by phosphorylating and inhibiting the nuclear translocation of the transcription factor EB (TFEB), which drives the expression of genes for lysosomal biogenesis and the autophagy machinery (Martina et al., 2012; RoczniakFerguson et al., 2012; Settembre et al.,”
mTOR: a pharmacologic target for autophagy regulation. (2015, neutral): “In contrast, mTORC1 phosphorylates ATG14L in the VPS34 complex and inhibits the lipid kinase activity of VPS34, providing another mTORC1-mediated mechanism in autophagy inhibition (73). mTORC1 also regulates autophagy at the transcriptional level by modulating localization of transcription factor EB”