During the AUTO-SELECT project, significant progress was made in elucidating the mechanisms governing cargo selectivity in autophagy, particularly focusing on endoplasmic reticulum (ER) turnover. A pivotal discovery was identifying the role of FAM134C, an ER-phagy receptor, in mediating selective ER degradation during nutrient deprivation. The research demonstrated that under normal conditions, casein kinase 2 (CK2) phosphorylates FAM134C at specific residues near its LC3-interacting region, reducing its affinity for autophagy-related proteins and thus inhibiting ER-phagy. Upon starvation, inhibition of mTORC1 signaling decreases this phosphorylation, thereby activating FAM134C and promoting ER-phagy. This mechanism was validated both in vitro and in vivo, with FAM134C knockout models revealing its critical role in regulating liver lipid metabolism during fasting. These findings enhance our understanding of autophagy's selectivity and its implications for metabolic health.
Building upon the AUTO-SELECT project's exploration of autophagy's cargo selectivity, recent research has unveiled a critical pathway by which cells manage misfolded protein accumulation within the endoplasmic reticulum (ER). This study highlights the role of SESTRIN2, a nutrient sensor that, upon activation by the ER stress sensor XBP1, inhibits mTORC1 signaling. This inhibition facilitates the nuclear translocation of transcription factors TFEB and TFE3, which subsequently upregulate the expression of the ER-phagy receptor FAM134B and lysosomal genes. The enhanced expression of FAM134B promotes the formation of a FAM134B-Calnexin complex, facilitating the selective degradation of misfolded proteins via ER-phagy. Notably, pharmacological activation of FAM134B has been shown to improve the clearance of these aberrant proteins, suggesting potential therapeutic avenues for ER storage disorders.
