1. MiT/TFE factors control ER-phagy via transcriptional regulation of FAM134B.
- Author
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Cinque L, De Leonibus C, Iavazzo M, Krahmer N, Intartaglia D, Salierno FG, De Cegli R, Di Malta C, Svelto M, Lanzara C, Maddaluno M, Wanderlingh LG, Huebner AK, Cesana M, Bonn F, Polishchuk E, Hübner CA, Conte I, Dikic I, Mann M, Ballabio A, Sacco F, Grumati P, and Settembre C
- Subjects
- Active Transport, Cell Nucleus, Animals, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors genetics, Cell Nucleus genetics, Endoplasmic Reticulum genetics, HeLa Cells, Humans, Intracellular Signaling Peptides and Proteins genetics, Mechanistic Target of Rapamycin Complex 1 genetics, Mechanistic Target of Rapamycin Complex 1 metabolism, Membrane Proteins genetics, Mice, Oryzias, Autophagy, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors metabolism, Cell Nucleus metabolism, Endoplasmic Reticulum metabolism, Intracellular Signaling Peptides and Proteins metabolism, Membrane Proteins metabolism, Signal Transduction
- Abstract
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 of ER-phagy receptors has shed light on the molecular mechanisms underlining this process. However, the signaling pathways regulating ER-phagy in response to cellular needs are still largely unknown. We found that the nutrient responsive transcription factors TFEB and TFE3-master regulators of lysosomal biogenesis and autophagy-control ER-phagy by inducing the expression of the ER-phagy receptor FAM134B. The TFEB/TFE3-FAM134B axis promotes ER-phagy activation upon prolonged starvation. In addition, this pathway is activated in chondrocytes by FGF signaling, a critical regulator of skeletal growth. FGF signaling induces JNK-dependent proteasomal degradation of the insulin receptor substrate 1 (IRS1), which in turn inhibits the PI3K-PKB/Akt-mTORC1 pathway and promotes TFEB/TFE3 nuclear translocation and enhances FAM134B 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 allows ER-phagy to respond to both metabolic and developmental cues., (© 2020 The Authors. Published under the terms of the CC BY 4.0 license.)
- Published
- 2020
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