Microautophagy mediated by lysosomal membrane proteins: insights from LAMP2B-dependent microlipophagy

Microautophagy involves the direct uptake of cytoplasmic materials by lysosomes, but its regulation, including substrate specificity, has remained largely unclear in mammalian cells. Microlipophagy, a form of lipid droplet microautophagy, has been suggested in mammalian cells, yet the molecular basis that links lysosomes to lipid droplets and supports their uptake has not been elucidated. In our recent study, we showed that the lysosomal membrane protein LAMP2B mediates this process via its cytoplasmic region, which can bind phosphatidic acid, a lipid present on lipid droplets. We also found that this pathway depends on the ESCRT machinery and proceeds independently of macroautophagy. In this commentary, we summarize these findings and describe how LAMP2B affects lipid droplet degradation in cells. We describe that LAMP2B overexpression protects mice from high-fat-diet-induced obesity and related disorders. We also outline a model of microautophagy and microautophagy-like processes in which LAMP2 isoforms use their cytoplasmic regions to recognize distinct cargos.