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bioRxiv · 10.1101/561001

A genome-wide screen for ER autophagy highlights key roles of mitochondrial metabolism and ER- resident UFMylation

Liang, J. R.·Lingeman, E.·Luong, T.·Ahmed, S.·Nguyen, T.·Olzmann, J.·Corn, J. E.
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Abstract

Selective degradation of organelles via autophagy 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 specialized autophagosomal receptors and remodelers. Using an ER-phagy reporter and genome-wide CRISPRi screening, we identified 200 high-confidence factors involved in human ER-phagy. We mechanistically investigated two pathways unexpectedly required for ER-phagy. First, reduced mitochondrial metabolism represses ER-phagy, which reverses the logic of general autophagy. Mitochondrial crosstalk with ER-phagy bypasses the energy sensor AMPK, instead directly impacting ULK1. Second, ER-localized UFMylation is required for ER-phagy that represses the unfolded protein response. The UFL1 ligase is brought to the ER surface by DDRGK1, analogous to PINK1-Parkin regulation during mitophagy. Our data provide insight into the unique 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.

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Liang, J. R., Lingeman, E., Luong, T., Ahmed, S., Nguyen, T., Olzmann, J., Corn, J. E.. 2019-02-25. A genome-wide screen for ER autophagy highlights key roles of mitochondrial metabolism and ER- resident UFMylation. https://doi.org/10.1101/561001

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