An N-terminal–truncated isoform of FAM134B (FAM134B-2) regulates starvation-induced hepatic selective ER-phagy

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.

MiT/ TFE factors control ER ‐phagy via transcriptional regulation of FAM 134B

“…FGF signaling controls ER-phagy in vivo. a transcriptional induction of Fam134b-2 by C/EBPb was recently shown to mediate starvation-induced ER-phagy in liver (Kohno et al, 2019), suggesting that multiple transcriptional circuitries might participate to the regulation of ER-phagy.…”

Critical roles of FAM134B in ER-phagy and diseases

“…In general, sheets correspond to rough ER (RER) and tubules to smooth ER (SER) 21 . However, in the liver, FAM134B-2 is expressed in both RER and SER, but more abundant in SER 3 . This is related to its regulation of ER-phagy of secretory proteins such as apolipoprotein C-III in liver 3 .…”

“…Protein FAM134B-2 is an N-terminally truncated isoform with just one transmembrane domain. Because it lacks the RHD, it cannot control the size of ER 3 . In mice, the expression of FAM134B-1 in brain tissue was much higher than that of FAM134B-2 3 .…”

“…Because it lacks the RHD, it cannot control the size of ER 3 . In mice, the expression of FAM134B-1 in brain tissue was much higher than that of FAM134B-2 3 . However, FAM134B-2, and not FAM134B-1, is dramatically increased in liver and peripheral tissues upon starvation and participates in starvation-induced hepatic ER-phagy 3 .…”

“…The LIR is responsible for binding with autophagosome while the RHD senses and induces ER membrane curvature. Based on this function, FAM134B participates in many ER-phagyrelated processes such as hepatic ER-phagy, quality control of procollagens, ER-to-lysosome-associated degradation (ERLAD), reticulo-mitophagy, and preadipocyte differentiation [3][4][5][6][7] . Moreover, FAM134B also acts as a cis-Golgi protein, although its specific function in the Golgi apparatus is not quite clear 8 .…”