Epithelial-Mesenchymal Transition Induces FAM134A-mediated ER-phagy to Regulate Procollagen Secretion

EMT is accompanied by extensive remodeling of the secretory pathway, yet how cancer cells maintain endoplasmic reticulum (ER) homeostasis during this transition remains unclear. Here we show that EMT activates ER-phagy as an adaptive mechanism to constrain secretory output. A genome-wide CRISPR activation screen unexpectedly identified EMT- and MET-associated transcription factors as opposing regulators of ER-phagy, and TGF{beta}-induced EMT robustly stimulated this pathway. Proteomic analysis revealed that ER-phagy regulates EMT-induced secretory protein degradation, including procollagens. Among FAM134 ER-phagy receptors, FAM134A uniquely mediated procollagen degradation through a non-canonical, LC3-independent mechanism. Loss of FAM134A diverted procollagen from degradation to secretion, resulting in a pro-invasive secretome, as conditioned media from FAM134A-deficient cells enhanced matrix invasion. These findings identify ER-phagy as a regulatory node that buffers EMT-associated secretory remodeling and reveal FAM134A as a context-specific suppressor of pro-invasive secretion.