MIT/TFE FACTORS CONTROL ER-PHAGY VIA TRANSCRIPTIONAL REGULATION OF FAM134B

Lysosomes are catabolic organelles devoted to the degradation of intracellular proteins and components. In addition, lysosomes are signalling hubs that orchestrate many intracellular responses. 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. ER-phagy receptors are ER membrane proteins or soluble proteins (such as CALCOCO1 and SQSTM1), that bind to cytosolic Atg8-family proteins via the LC3-Interacting Region (LIR) mediating the delivery of specific ER subdomains to lysosomes for degradation. Although the role of the ER-phagy in the regulation of ER size and cellular proteostasis has been well characterized, the upstream signalling pathway regulating ER-phagy in response to developmental and cellular needs is still largely unknown. Chondrocytes are highly secretory cells with an abundant ER, producing predominantly procollagen (PC) molecules in extracellular matrix during endochondral ossification. They reside in a poorly vascularized tissue, as the growth plate, with scarcity of nutrients, representing a good cellular model to study ER-phagy. 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 is activated in chondrocytes by FGF signalling, a critical regulator of skeletal growth. We demonstrated that FGF18 induces lysosome biogenesis and ER-phagy in chondrocytes through the activation of FGFR3 and FGFR4 receptors, which in turn inhibit the PI3K/Akt-mTORC1 pathway and promote TFEB/TFE3 nuclear translocation and enhance Fam134b transcription. Notably, FAM134B is required for protein secretion in chondrocytes. In conclusion, this study identifies a new signalling pathway that allows ER-phagy to respond to developmental cues suggesting potential therapeutic approaches for the treatment of skeletal features in multiple human diseases.