Regulation of endoplasmic reticulum turnover by selective autophagy

Abstract

The turnover of endoplasmic reticulum (ER) ensures the correct biological activity of its distinct domains. In mammalian cells, the ER is degraded via a selective autophagy pathway (ER-phagy), mediated by two specific receptors: FAM134B, responsible for the turnover of ER sheets and SEC62 that regulates ER recovery following stress. Here, we identified reticulon 3 (RTN3) as a specific receptor for the degradation of ER tubules. Oligomerization of the long isoform of RTN3 is sufficient to trigger fragmentation of ER tubules. The long N-terminal region of RTN3 contains several newly identified LC3-interacting regions (LIR). Binding to LC3s/GABARAPs is essential for the fragmentation of ER tubules and their delivery to lysosomes. RTN3-mediated ER-phagy requires conventional autophagy components, but is independent of FAM134B. None of the other reticulon family members have the ability to induce fragmentation of ER tubules during starvation. Therefore, we assign a unique function to RTN3 during autophagy.

Increased transport of acetyl‐CoA into the endoplasmic reticulum causes a progeria‐like phenotype

“…To address the above scenario and dissect the mechanism responsible for the block in reticulophagy, we studied levels and ER association of Fam134b, a recently identified key regulator of reticulophagy (Khaminets et al, 2015; Mochida et al, 2015; Rubinsztein, 2015). Interestingly, the ER expansion in AT‐1 sTg mice was accompanied by a marked increase in the number of Fam134b puncta on the ER membrane (Figure 5d,e).…”

“…The upregulation of Fam134b in AT‐1 sTg mice was also observed when we analyzed mRNA (Figure 5f) and protein levels (Figure 5g,h). Fam134b has recently emerged as a novel regulator of ER‐autophagy, and levels of Fam134b seem to reflect intrinsic dynamics of reticulophagy (Khaminets et al, 2015; Lennemann & Coyne, 2017; Mochida et al, 2015; Nakatogawa & Mochida, 2015; Rubinsztein, 2015). Therefore, increased steady‐state levels of Fam134b in AT‐1 sTg mice (Figure 5d–h) are consistent with the observed ER expansion (Figure 5c and Supporting Information Figure S3d), as they might reflect reduced turnover of the ER‐associated Fam134b protein as well as an attempt of the cell to restore reticulophagy by activating Fam134b translation.…”

“…Therefore, increased steady‐state levels of Fam134b in AT‐1 sTg mice (Figure 5d–h) are consistent with the observed ER expansion (Figure 5c and Supporting Information Figure S3d), as they might reflect reduced turnover of the ER‐associated Fam134b protein as well as an attempt of the cell to restore reticulophagy by activating Fam134b translation. Fam134b has a LC3‐interacting region (LIR) on its C‐terminus, which is required for binding to cytosolic LC3β (also referred to as Atg8 in yeast; Khaminets et al, 2015; Mochida et al, 2015; Rubinsztein, 2015). Fam134b‐LC3β interaction is required for efficient induction of reticulophagy (Khaminets et al, 2015; Mochida et al, 2015; Rubinsztein, 2015).…”

“…Fam134b has a LC3‐interacting region (LIR) on its C‐terminus, which is required for binding to cytosolic LC3β (also referred to as Atg8 in yeast; Khaminets et al, 2015; Mochida et al, 2015; Rubinsztein, 2015). Fam134b‐LC3β interaction is required for efficient induction of reticulophagy (Khaminets et al, 2015; Mochida et al, 2015; Rubinsztein, 2015). Notably, despite the increased levels of Fam134b, we observed a marked reduction in Fam134b‐LC3β co‐localization in AT‐1 sTg vs. WT (Figure 5i,j).…”

“…Fam134b is an integral ER membrane protein that acts as a “receptor” for reticulophagy (Khaminets et al, 2015; Mochida et al, 2015; Rubinsztein, 2015). It was recently identified in both yeast and mammalian cells (Khaminets et al, 2015; Mochida et al, 2015; Rubinsztein, 2015).…”