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.

中文翻译：

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MiT / TFE因子通过FAM134B的转录调控来控制ER吞噬。

内质网（ER）通过自噬（ER-phagy）的溶酶体降解正在成为细胞稳态和功能的重要调节剂。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，响应于细胞需求调节ER-噬菌体的信号传导途径仍是未知之数。我们发现营养反应性转录因子TFEB和TFE3（溶酶体生物发生和自噬的主要调节剂）通过诱导ER噬菌体受体FAM134B的表达来控制ER噬菌体。长期饥饿时，TFEB / TFE3-FAM134B轴可促进ER吞噬激活。另外，该途径在软骨细胞中被FGF信号传导激活，而FGF信号传导是骨骼生长的关键调节剂。FGF信号传导诱导胰岛素受体底物1（IRS1）的JNK依赖性蛋白酶体降解，进而抑制PI3K-PKB / Akt-mTORC1途径并促进TFEB / TFE3核易位并增强FAM134B转录。值得注意的是，FAM134B是软骨细胞中蛋白质分泌以及鱼中软骨生长和骨骼矿化所必需的。这项研究确定了一条新的信号通路，可使ER吞噬对代谢和发育线索做出反应。