The Transcription Factor TFEB Links mTORC1 Signaling to Transcriptional Control of Lysosome Homeostasis

By Agnes Roczniak-Ferguson, Constance S. Petit, Florian Froehlich, Sharon Qian, Jennifer Ky, B. Angarola, T. Walther, S. Ferguson. Science Signaling, 2012

1,306 citations recorded by the source corpus.

The nuclear translocation of a transcription factor that promotes lysosomal biogenesis is inhibited when lysosomal function is adequate. Sensing Lysosomal Status Lysosomes clear cells of damaged organelles, cellular debris, and internalized materials. Lysosomal biogenesis requires the transcription factor TFEB, and Roczniak-Ferguson et al. investigated the mechanisms by which lysosomal status controlled the activity of TFEB. They found that TFEB interacted with mTOR (mechanistic target of rapamycin), a kinase that localizes to lysosomes. The mTOR-dependent phosphorylation of TFEB caused TFEB to interact with 14-3-3 proteins, which led to the retention of the transcription factor in the cytoplasm. When lysosomal function was inhibited, TFEB no longer interacted with mTOR, was dephosphorylated, and translocated to the nucleus. Thus, the localization (and thus activity) of TFEB is determined by mTOR-mediated phosphorylation, which in turn reflects lysosomal status. Lysosomes are the major cellular site for clearance of defective organelles and digestion of internalized material. Demand on lysosomal capacity can vary greatly, and lysosomal function must be adjusted to maintain cellular homeostasis. Here, we identified an interaction between the lysosome-localized mechanistic target of rapamycin complex 1 (mTORC1) and the transcription factor TFEB (transcription factor EB), which promotes lysosome biogenesis. When lysosomal activity was adequate, mTOR-dependent phosphorylation of TFEB on Ser211 triggered the binding of 14-3-3 proteins to TFEB, resulting in retention of the transcription factor in the cytoplasm. Inhibition of lysosomal function reduced the mTOR-dependent phosphorylation of TFEB, resulting in diminished interactions between TFEB and 14-3-3 proteins and the translocation of TFEB into the nucleus, where it could stimulate genes involved in lysosomal biogenesis. These results identify TFEB as a target of mTOR and suggest a mechanism for matching the transcriptional regulation of genes encoding proteins of autophagosomes and lysosomes to cellular need. The closely related transcription factors MITF (microphthalmia transcription factor) and TFE3 (transcription factor E3) also localized to lysosomes and accumulated in the nucleus when lysosome function was inhibited, thus broadening the range of physiological contexts under which this regulatory mechanism may prove important.

Subfields: Cell Biology, Epidemiology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/fb0114c388be2eee3c3293341179a564161f776a

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Citations in the corpus

Handbook of ion channels (2015, background): “Interestingly, lysosome biogenesis is also regulated by a master growth-regulated kinase mechanistic target of rapamycin (mTOR) (64) and a lysosome-associated transcription factor TFEB (65).”
Autophagy and Neurodegeneration: Pathogenic Mechanisms and Therapeutic Opportunities. (2017, neutral): “In resting cells, phosphorylation of TFEB by active mTORC1 induces TFEB binding to 14-3-3 proteins and therefore TFEB retention in the cytosol (Roczniak-Ferguson et al., 2012; Settembre et al., 2011).”
mTOR Signaling in Growth, Metabolism, and Disease. (2017, background): “…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., 2012).”
TFEB at a glance (2016, background): “Accordingly, variants of TFEB carrying Ser-to-Ala mutations of either Ser142 or Ser211 are always nuclear and constitutively active (Martina et al., 2012; Roczniak-Ferguson et al., 2012; Settembre et al., 2011, 2012).”
Regulation of mTORC1 and its impact on gene expression at a glance (2013, background): “Recently, mTORC1 has been identified as a key regulator of TFEB function (Martina et al., 2012; Roczniak-Ferguson et al., 2012; Settembre et al., 2012).”
The Nutrient-Responsive Transcription Factor TFE3, Promotes Autophagy, Lysosomal Biogenesis, and Clearance of Cellular Debris (2014, background): “In contrast, under starvation conditions, mTORC1 is inactivated, the TFEB and 14-3-3 complex dissociates, and TFEB translocates to the nucleus, where it stimulates the expression of hundreds of genes, thus leading to lysosomal biogenesis, increased lysosomal degradation, and autophagy induction (13,”
Phosphatidylinositol-5-phosphate 4-kinases regulate cellular lipid metabolism by facilitating autophagy (2018, background): “When nutrients are present, mTORC1 phosphorylates TFEB, which localizes TFEB to the cytoplasm (Roczniak-Ferguson et al., 2012; Settembre et al., 2012).”
The lysosome: from waste bag to potential therapeutic target. (2013, background): “In response to impaired cellular energy status mTOR dependent phosphorylation of TFEB is interrupted allowing transcriptional regulation of genes encoding proteins needed for autophagosome formation and increased autophagic flux (Roczniak-Ferguson et al., 2012).”
Recent insights into the function of autophagy in cancer (2016, background): “SAR405 binds the hydrophobic cleft of the active site and is highly selective for Vps34.”
TFEB-mediated autophagy rescues midbrain dopamine neurons from α-synuclein toxicity (2013, background): “The fact that α-syn shares both structural and functional homology with 14-3-3 proteins (46, 47), and the recent finding that phosphorylated TFEB is sequestered in the cytoplasm by 14-3-3 proteins (38), suggests an possible pathogenic mechanism where increased cytoplasmic levels of α-syn could bind ”