Regulated compartmentalization of enzymes in Golgi by GRASP55 controls cellular glycosphingolipid profile and function

Glycans are important regulators of cell and organismal physiology. This requires that the glycan biosynthesis be controlled to achieve specific cellular glycan profiles. Glycans are assembled in the Golgi apparatus on secretory cargoes that traverse it. The mechanisms by which Golgi apparatus ensures cell and cargo-specific glycosylation remain obscure. We investigated how Golgi apparatus regulates glycosylation by studying biosynthesis of glycosphingolipids, glycosylated lipids with critical roles in signalling and differentiation. Glycosylation enzymes have compartmentalized localization in the Golgi stack, but the molecular machineries involved are unknown. We identified Golgi matrix protein GRASP55 as a prototype controller of Golgi enzyme localization that specifically binds and compartmentalizes key glycosphingolipid biosynthetic enzymes by promoting their anterograde transport in the Golgi. Impairing GRASP55-enzyme interaction decompartmentalizes these enzymes, changes the cargo flux across competing glycosylation pathways that results in alteration of cellular glycosphingolipid profile. This GRASP55 regulated pathway of enzyme compartmentalization allows cells to make cell density dependent adaptations to glycosphingolipid biosynthesis to suit cell growth needs. Thus, Golgi apparatus controls cellular glycan (glycosphingolipid) profile by governing competition between biosynthetic reactions through regulated changes in enzyme compartmentalization.