MiT/TFE factors control ER-phagy via transcriptional regulation of FAM134B
MiT/TFE factors control ER-phagy via transcriptional regulation of FAM134B
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DOI：
10.15252/embj.2020105696
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发表时间：
2020-07-27
期刊：
影响因子：
11.4
通讯作者：
Settembre, Carmine
中科院分区：
文献类型：
--
作者：
Cinque, Laura;Leonibus, Chiara;Settembre, Carmine
内质网（ER）通过自噬（ER-吞噬）的溶酶体降解正在成为细胞稳态和功能的关键调节剂。最近对ER-吞噬受体的鉴定揭示了这一过程的分子机制。然而，调节ER-吞噬反应细胞需要的信号通路仍然是未知的。我们发现营养应答转录因子TFE3和TFE3-通过诱导ER-吞噬受体FAM134 B的表达，成为溶酶体生物发生和自噬控制ER-吞噬的主要调节因子。TFEB/TFE3-FAM134B轴促进长期饥饿时ER-吞噬激活。此外，软骨细胞中的这一通路还被骨骼生长的关键调节因子FGF信号所激活，FGF信号诱导JNK依赖的蛋白酶体降解胰岛素受体底物1（IRS1），进而抑制PI3K-PKB/Akt-mTORC1通路，促进TFEB/TFE3核转位，增强FAM134B的转录。值得注意的是，FAM134 B是青鳉鱼软骨细胞中蛋白质分泌、软骨生长和骨矿化所必需的。这项研究确定了一个新的信号通路，允许ER-吞噬反应的代谢和发育线索。
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.