ER remodeling via ER-phagy

Abstract

The endoplasmic reticulum (ER) is a hotspot for many essential cellular functions. The ER membrane is highly dynamic, which affects many cellular processes that take place within the ER. One such process is ER-phagy, a selective degradation of ER fragments (including membranes and luminal content), which serves to preserve the size of ER while adapting its morphology under basal and stress conditions. In order to be degraded, the ER undergoes selective fragmentation facilitated by specialized ER-shaping proteins that also act as ER-phagy receptors. Their ability to sense and induce membrane curvature, as well as to bridge the ER with autophagy machinery, allows for a successful ER fragmentation and delivery of these fragments to the lysosome for degradation and recycling. In this review, we provide insights into ER-phagy from the perspective of membrane remodeling. We highlight the importance of ER membrane dynamics during ER-phagy and emphasize how its dysregulation reflects on human physiology and pathology.

Graphical abstract

Figure 1

Schematic representation of processes relying on ER remodeling Some of the processes that rely on ER remodeling as part of their mechanism (highlighted in light blue), separated by the dashed lines, even though in reality they do overlap in most cases. From left to right, ER tubule formation, three-way junction formation, vesicular trafficking, unfolded protein response and ERAD, ER-organelle contact-site formation, ER-phagy and ERLAD are only some of the processes essential for cellular function, which require or induce changes to ER morphology.

Figure 2

Schematic representation of ER-phagy and reticulon-homology domains (A) FAM134B, the best characterized RHD-containing ER-phagy receptor, can oligomerize, sense, and induce membrane curvature. High concentration of FAM134B leads to membrane budding, which is recognized by the autophagy machinery through direct binding between FAM134B and LC3/GABARAP proteins. This binding provides additional forces that lead to scission of these ER membrane buds and their subsequent incorporation into the forming autophagosome. The autophagosome will fuse with a lysosome, where the fragmented ER membrane and embedded RHD-containing proteins are degraded. (B) RHDs assume a wedge-shaped form when inserted into the ER membrane. RHDs consist of two conserved transmembrane hairpins (TM1,2 and TM3,4) and two amphipathic helices (AH-L and AH-C). AH-L is part of a linker sequence, connecting TM1,2 and TM3,4, and AH-C is localized C-terminally of TM3,4. The transmembrane hairpins locally compress the lipid bilayer, while the amphipathic helices allow stretching of the cytosolic leaflet to induce strong local membrane deformations.