Lipid Codes and Lipid-Binding Proteins as Central Regulators of Autophagy

Autophagy is increasingly understood as a lipid-governed membrane program rather than a solely protein-driven degradative pathway. This review combines molecular and mechanistic evidence showing how lipid molecules, metabolic enzymes, and membrane physical properties coordinate autophagy from induction to lysosomal degradation. We highlight phosphoinositide microdomains and their cognate kinases and phosphatases as spatial cues that nucleate phagophores, control maturation, and regulate lysosome reformation. We also discuss alternative phosphoinositide sources, sphingolipid and ceramide signaling, phosphatidic acid and diacylglycerol metabolism, fatty-acyl composition, and acyl-CoA signaling as determinants of membrane curvature, tension, leaflet asymmetry, and phase behavior in autophagy. Key protein effectors and their lipid binding motifs and domains are integrated into a model in which lipid chemistry and mechanics gate enzymatic activities. We present integrated lipid-protein-biophysics approaches to highlight outstanding questions and uncover predictive principles.