Autophagy is a catabolic process for the disposal of cytoplasmic contents that are captured by double-membrane autophagosomes and delivered to lysosomes for degradation. The steps involved in canonical autophagy have been well studied over the last 30 years and include complexes involved in the initiation of a phagophore, sequestration of cargo, elongation and maturation of the autophagosome, and fusion with the lysosome.
More recently, it has been recognized that autophagy can take place in a selective manner that permits the degradation of specific targets and organelles. Known as selective autophagy, it is generally achieved using specialized autophagy cargo receptors containing LC3-interacting regions (LIR) or GABARAP-interacting motifs (GIM) that associate with LC3/GABARAP family members on the phagophore. One of these selective autophagy processes that has gained interest recently has been the targeted degradation of fragments of the endoplasmic reticulum (ER) through a process referred to as ER-phagy or reticulophagy.
What is the ER-phagy and how is it regulated?
The ER is a large multifaceted organelle that functions in protein folding and processing, calcium storage, and steroid and lipid biogenesis. It is composed of a heterogeneous and continuous network of flattened sacs, or sheets, and tubules that extend from the nuclear envelope to the plasma membrane. It can be divided into the rough ER and the smooth peripheral ER—the rough ER is predominantly within perinuclear sheets and decorated with ribosomes, while the smooth peripheral ER is involved in metabolic activities such as lipid and steroid synthesis. The tubular ER extends throughout the cytoplasm and provides contact points for signaling to other organelles including providing lipids for phagophore formation needed for autophagy.
Learn more about autophagy using our interactive signaling pathway.
The ER structure is regulated in a dynamic fashion to maintain homeostasis and adjust to cellular stress. Defects in this process may contribute to pathological conditions including metabolic and neurological disorders, cancer, and impairments to defense against infectious diseases.
ER-phagy is one of the key processes that regulates ER morphology and functions in the fragmentation and removal of ER segments. Accumulation of unfolded proteins or exposure to conditions such as metabolic or oxidative stress lead to compensatory ER stress programs that remodel the ER structure and activate signaling pathways to cope with those challenges. Activation of ER stress pathways, such as the unfolded protein response (UPR), increases ER membrane to help manage increased demand. Once the stress conditions subside, ER-phagy can eliminate unneeded ER fragments.1-3
ER-Resident Autophagy Receptors
Over the last several years, there have been advances in our understanding of ER-phagy. A significant advancement is the discovery of several ER-resident autophagy receptors, including FAM134B, CCPG1, ATL3, TEX264, SEC62, and RTN3L. These cargo receptors have distinct modes of regulation, expression, and localization patters within the ER. Each of these proteins contains at least one LIR or GIM, which facilitates binding to LC3 or GABARAP family members on the autophagosome. These autophagy receptors contribute to ER-phagy at specific sites on the ER and in response to different stimuli, including nutrient deprivation, ER stress, and changes in calcium. Loss of these proteins is associated with damaged ER expansion, sustained activation of ER stress pathways, and pathophysiological regulation.
The Role of FAM134B
FAM134B was the first ER-phagy discovered and it is the best characterized to date. Loss of FAM134B can sensitize cells to apoptosis when challenged by nutrient deprivation or ER stress stimuli. It is predominantly localized to ER sheets illustrative of the site-specific roles of the autophagy cargo receptors. Deletion of FAM134 has been linked to hereditary sensory and autonomic neuropathy (HSAN). FAM134B has also been linked to cancer, but the role it plays here may be dependent on the cancer type. Oncogenic activity of FAM134B has been linked to esophageal and hepatocellular carcinoma, and tumor-suppressive properties were reported in colorectal and breast carcinoma. Recently, FAM134B has gained interest due to its role in viral infection. In general, ER-phagy is believed to function as a host defense mechanism to eliminate viruses and bacteria. Interestingly, some pathogens have evolved mechanisms to directly subvert ER-phagy, such as the Dengue and Zika viruses, which encode a protease, NS2B3, that cleaves FAM134B to inhibit its activity.
Following the discovery of FAM134B, several additional ER-phagy cargo receptors have been identified that can regulate ER-phagy at different sites, under different stimuli, and different cell types. While FAM134B primarily mediates degradation of ER sheets, other ER autophagy cargo receptors, like RTN3L and ATL3, mediate degradation of tubular ER. CCPG1 has gained interest as a cargo receptor that is transcriptionally regulated in response to ER stress. CCPG1 also binds to FIP200 as a potential alternative mechanism for recruitment of autophagic machinery. There is also increasing awareness that post-translational modifications help regulate ER-phagy. Of note here, under conditions of ER stress, FAM134B is phosphorylated, which facilitates ER-phagy. More recently, using a novel ER-phagy fluorescent reporter assay, Liang et al. identified a role for UFMylation in promoting ER-phagy. Downstream signaling of UFMylation is an area that requires further exploration.
Many questions about ER-phagy remain, including factors that trigger ER-phagy, the role of post-translational modifications such as phosphorylation, ubiquitination, and UFMylation, and the role that it has in disease and potential therapeutic intervention. Cell Signaling Technology (CST) is helping researchers answer these important issues by providing fully validated antibodies to study ER cargo receptors, canonical autophagy regulators, and markers of ER stress.
Additional Resources
Read other blogs in our autophagy series:
- Autophagy: Taking Out the Cellular Trash Has Widespread Therapeutic Implications
- Understanding Mitophagy
- Xenophagy: What You Eat Can't Hurt You
Select References
- Ferro-Novick S, Reggiori F, Brodsky JL. ER-Phagy, ER Homeostasis, and ER Quality Control: Implications for Disease. Trends Biochem Sci. 2021;46(8):630-639. doi:10.1016/j.tibs.2020.12.013
- Hübner CA, Dikic I. ER-phagy and human diseases. Cell Death Differ. 2020;27(3):833-842. doi:10.1038/s41418-019-0444-0
- Chino H, Mizushima N. ER-Phagy: Quality Control and Turnover of Endoplasmic Reticulum. Trends Cell Biol. 2020;30(5):384-398. doi:10.1016/j.tcb.2020.02.001
- Liang JR, Lingeman E, Luong T, et al. A Genome-wide ER-phagy Screen Highlights Key Roles of Mitochondrial Metabolism and ER-Resident UFMylation. Cell. 2020;180(6):1160-1177.e20. doi:10.1016/j.cell.2020.02.017
- Mo J, Chen J, Zhang B. Critical roles of FAM134B in ER-phagy and diseases. Cell Death Dis. 2020;11(11):983. Published 2020 Nov 16. doi:10.1038/s41419-020-03195-1
- Wilkinson S. Emerging Principles of Selective ER Autophagy. J Mol Biol. 2020;432(1):185-205. doi:10.1016/j.jmb.2019.05.012
