Liang, J. R.; Di Monaco, M.; Vascon, A.; Sen, O.; Peteri, M.; Saksono, G.; Soares, R.; Squires, I.; Brunner, V.; Schellhaas, C.; Ulrich, S.; Teo, J. Y.; Corn, J.

The selective turnover of endoplasmic reticulum via autophagy (ER-phagy) is a fundamentally important pathway that is activated under different stresses to remove misfolded ER proteins or excess ER to ensure overall ER and cellular fitness. Dysregulation of many ER-phagy receptors has been implicated in neurodevelopmental defects, tissue inflammation, and cancer progression. However, additional ER-phagy regulators beyond these ER surface receptors remained under- explored. Using a CRISPR-activation approach, we performed a genome-wide gain-of-function screen, which led to the unexpected discovery of Epithelial-to-Mesenchymal Transition (EMT) and Mesenchymal-to-Epithelial Transition (MET)-associated transcription factors as opposing regulators of ER-phagy. We further demonstrated that TGF{beta}, a physiological EMT activator, also induces ER-phagy. Using proteomics, we found that EMT-induced ER-phagy is required to regulate procollagen degradation. Among FAM134 paralogues which are known ER-phagy receptors, only FAM134A is able to mediate procollagen degradation via a non-canonical, LC3-interacting motif (LIR)-independent manner during EMT. Knockdown of FAM134A reroutes procollagen from ER-phagy to secretion. We further showed that this increase in secretion during EMT promotes matrix invasion. Our findings highlight ER-phagy as an adaptive mechanism during cell state transitions and uncover a context-specific role for FAM134A in modulating the secretory proteome.