MiT/TFEfactors controlER-phagy via transcriptional regulation ofFAM134B
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- MiT/TFE factors control ER-phagy via transcriptional regulation of FAM134B
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Lysosomal degradation of the endoplasmic reticulum (ER) via autophagy (ER-phagy) is emerging as a critical regulator of cell homeostasis and function. The recent identification ofER-phagy receptors has shed light on the molecular mechanisms underlining this process. However, the signaling pathways regulatingER-phagy in response to cellular needs are still largely unknown. We found that the nutrient responsive transcription factorsTFEBandTFE3-master regulators of lysosomal biogenesis and autophagy-controlER-phagy by inducing the expression of theER-phagy receptorFAM134B. TheTFEB/TFE3-FAM134B axis promotesER-phagy activation upon prolonged starvation. In addition, this pathway is activated in chondrocytes byFGFsignaling, a critical regulator of skeletal growth.FGFsignaling inducesJNK-dependent proteasomal degradation of the insulin receptor substrate 1 (IRS1), which in turn inhibits thePI3K-PKB/Akt-mTORC1 pathway and promotesTFEB/TFE3 nuclear translocation and enhancesFAM134B transcription. Notably,FAM134B is required for protein secretion in chondrocytes, and cartilage growth and bone mineralization in medaka fish. This study identifies a new signaling pathway that allowsER-phagy to respond to both metabolic and developmental cues.
Original language | English |
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Article number | 105696 |
Journal | EMBO Journal |
Volume | 39 |
Issue number | 17 |
Number of pages | 22 |
ISSN | 0261-4189 |
DOIs | |
Publication status | Published - 2020 |
- ER-phagy, Fam134B, FGFsignaling, IRS1, PI3K signaling, TFEB, ENDOPLASMIC-RETICULUM, BONE-GROWTH, ER-PHAGY, AUTOPHAGY, RECEPTOR, MECHANISM, NETWORK, TEX264, FGF
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