Abstract
Autophagy is a conserved system that adapts to nutrient starvation, after which proteins and organelles are degraded to recycle amino acids in response to starvation. Recently, the ER was added to the list of targets of autophagic degradation. Autophagic degradation pathways of bulk ER and the specific proteins sorted through the ER are considered key mechanisms in maintaining ER homeostasis. Four ER-resident proteins (FAM134B, CCPG1, SEC62, and RTN3) have been identified as ER-resident cargo receptors, which contain LC3-interacting regions. In this study, we identified an N-terminal-truncated isoform of FAM134B (FAM134B-2) that contributes to starvation-induced ER-related autophagy. Hepatic FAM134B-2 but not full-length FAM134B (FAM134B-1) is expressed in a fed state. Starvation drastically induces FAM134B-2 but no other ER-resident cargo receptors through transcriptional activation by C/EBPβ. C/EBPβ overexpression increases FAM134B-2 recruitment into autophagosomes and lysosomal degradation. FAM134B-2 regulates lysosomal degradation of ER-retained secretory proteins such as ApoCIII. This study demonstrates that the C/EBPβ-FAM134B-2 axis regulates starvation-induced selective ER-phagy.
Highlights
The ER is the most abundant membrane structure in the cell
We performed quantitative reverse transcription PCR to determine which hepatic ER-resident cargo receptor is transcriptionally regulated upon starvation. 16 h of fasting selectively increased mRNA levels of family with sequence similarity 134 member B (FAM134B), which were normalized by 6 h of re-feeding (Fig 1A)
The antibody recognizes the C-terminal region of the FAM134B protein, suggesting that the truncation occurs at the N-terminal of the protein
Summary
The ER is the most abundant membrane structure in the cell. The ER is the central organelle that regulates protein synthesis and modification, lipid metabolism, and calcium homeostasis (Borgese et al, 2006; Braakman & Hebert, 2013; Krebs et al, 2015). ER-resident membrane proteins family with sequence similarity 134 member B (FAM134B), preprotein translocation factor (SEC62), cell cycle progression protein 1 (CCPG1), and reticulon 3 (RTN3) were identified as ER-phagy receptors (Khaminets et al, 2015; Fumagalli et al, 2016; Grumati et al, 2017; Fregno & Molinari, 2018; Smith et al, 2018). These proteins contain LC3-interacting regions in a cytosolic domain and mediate autophagic cargo followed by lysosomal degradation
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