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Significance Autophagy involves multiple fusion events, from autophagosome formation to autophagosome-lysosome fusion in a Ca2+-dependent manner. Fundamental unanswered issue- in the autophagy field is how Ca2+ is provided for autophagic… Click to show full abstract
Significance Autophagy involves multiple fusion events, from autophagosome formation to autophagosome-lysosome fusion in a Ca2+-dependent manner. Fundamental unanswered issue- in the autophagy field is how Ca2+ is provided for autophagic membrane fusion. Here, we report that transient receptor potential mucolipin 3 (TRPML3) is the Ca2+ release channel in the phagophore during autophagy. Notably, TRPML3 functions as a downstream effector of phosphatidylinositol-3-phosphate (PI3P), an essential lipid enriched at the phagophore upon autophagy induction; PI3P interacted with and activated TRPML3, resulting in Ca2+ release from the phagophore to promote autophagy. We also show the unique lipid regulation of TRPML3 by identifying its unusual PI3P-binding site. We believe our findings contribute to a deeper understanding of autophagy and lipid regulation of the ion channel.