Highlights d The Fab1 lipid kinase is a substrate of the Target of Rapamycin Complex 1 (TORC1) d Fab1 and TORC1 localize to signaling endosomes and the vacuole d Fab1 phosphorylation shifts TORC1 to signaling endosomes and changes its activity d Fab1 and TORC1 function in a regulatory feedback loop, which controls signaling

Haploinsufficiency of GRN causes frontotemporal dementia (FTD). The GRN locus produces progranulin (PGRN), which is cleaved to lysosomal granulin polypeptides. The function of lysosomal granulins and why their absence causes neurodegeneration are unclear. Here we discover that PGRN-deficient human cells and murine brains, as well as human frontal lobes from GRN-mutation FTD patients have increased levels of gangliosides, glycosphingolipids that contain sialic acid. In these cells and tissues, levels of lysosomal enzymes that catabolize gangliosides were normal, but levels of bis(monoacylglycero)phosphates (BMP), lipids required for ganglioside catabolism, were reduced with PGRN deficiency. Our findings indicate that granulins are required to maintain BMP levels to support ganglioside catabolism, and that PGRN deficiency in lysosomes leads to gangliosidosis. Lysosomal ganglioside accumulation may contribute to neuroinflammation and neurodegeneration susceptibility observed in FTD due to PGRN deficiency and other neurodegenerative diseases.

Eukaryotic cells rely on a set of membrane-enclosed organelles to perform highly efficient reactions in an optimized environment. Trafficking of molecules via vesicular carriers and membrane contact sites (MCS) allow the coordination between these compartments, though the precise mechanisms are still enigmatic. Among the cellular organelles, the lysosome/vacuole stands out as a central hub, where multiple pathways merge. Importantly, the delivered material is degraded and the monomers are recycled for further usage, which explains its wide variety of roles in controlling cellular metabolism. We will highlight recent advances in the field by focusing on the yeast vacuole as a model system to understand lysosomal function in general.