Author response: Full length RTN3 regulates turnover of tubular endoplasmic reticulum via 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 (ERphagy), 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.

A Dual Binding Receptor for ER-phagy

“…From a more mechanistic perspective, questions remain regarding how these receptors function and whether they can cleave ER membranes prior to sequestration. Although curvature-creating proteins (e.g., reticulon-like proteins) can cause membrane tubulation and fragmentation (Mochida et al, 2015;Khaminets et al, 2015;Grumati et al, 2017), mechanical force caused by autophagosomal closure may induce ER fission, as has been recently reported for mitochondria (Helle et al, 2017). Finally, it would also be interesting to investigate the role of the ER-phagy receptors in the context of autophagic membrane elongation.…”

“…Atg39 can also mediate degradation of a portion of the nucleus. In mammals, three ER-phagy receptors have been identified thus far: FAM134B, a reticulon-like protein (Khaminets et al, 2015); SEC62, a component of the ER translocon (Fumagalli et al, 2016); and reticulon 3 (RTN3) (Grumati et al, 2017). Common to these three receptors is the presence of both LIR/AIM(s) and ER-anchored domain(s) to bridge the ER and autophagosomal membranes (Figure 1).…”

“…Despite their shared features, the mammalian ER-phagy receptors appear to serve distinct functions. Because FAM134B is present on sheet ER and RTN3 on tubular ER, these ERphagy receptors are involved in degradation of these respective parts of the ER (Khaminets et al, 2015;Grumati et al, 2017). SEC62 is important for ER-phagy during the recovery phase from ER stress conditions (Fumagalli et al, 2016).…”