A Genome-wide ER-phagy Screen Highlights Key Roles of Mitochondrial Metabolism and ER-Resident UFMylation

• Published in: Cell 2020-03, Vol.180 (6), p.1160-1177.e20
• Main Authors: Liang, Jin Rui, Lingeman, Emily, Luong, Thao, Ahmed, Saba, Muhar, Matthias, Nguyen, Truc, Olzmann, James A., Corn, Jacob E.
• Format: Article
• Language: English
• Subjects: autophagy; Autophagy - genetics; Autophagy - physiology; CRISPR; endoplasmic reticulum; Endoplasmic Reticulum - genetics; Endoplasmic Reticulum - metabolism; Endoplasmic Reticulum Stress - physiology; Endoribonucleases - metabolism; ER-phagy; Genome-Wide Association Study - methods; genome-wide screen; HCT116 Cells; HEK293 Cells; HeLa Cells; Homeostasis; Humans; Membrane Proteins - metabolism; Mitochondria - genetics; Mitochondria - metabolism; organelle turnover; oxidative phosphorylation; post-translational modification; Protein-Serine-Threonine Kinases - metabolism; Proteins - metabolism; Ribosomal Proteins - metabolism; UFMylation; Unfolded Protein Response - physiology
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2020.02.017

Selective autophagy of organelles is critical for cellular differentiation, homeostasis, and organismal health. Autophagy of the ER (ER-phagy) is implicated in human neuropathy but is poorly understood beyond a few autophagosomal receptors and remodelers. By using an ER-phagy reporter and genome-wide CRISPRi screening, we identified 200 high-confidence human ER-phagy factors. Two pathways were unexpectedly required for ER-phagy. First, reduced mitochondrial metabolism represses ER-phagy, which is opposite of general autophagy and is independent of AMPK. Second, ER-localized UFMylation is required for ER-phagy to repress the unfolded protein response via IRE1α. The UFL1 ligase is brought to the ER surface by DDRGK1 to UFMylate RPN1 and RPL26 and preferentially targets ER sheets for degradation, analogous to PINK1-Parkin regulation during mitophagy. Our data provide insight into the cellular logic of ER-phagy, reveal parallels between organelle autophagies, and provide an entry point to the relatively unexplored process of degrading the ER network. [Display omitted] •Genome-wide CRISPRi screen identifies 200 high-confidence ER-phagy regulators•Disruption of mitochondrial OXPHOS system inhibits ER-phagy•ER-resident UFMylation mediates autophagy of the ER sheets An unbiased, genome-wide screen implicates mitochondrial oxidative phosphorylation and ER surface UFMylation as regulators of starvation-induced ER-phagy.