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

Abstract

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 the Golgi apparatus ensures cell- and cargo-specific glycosylation remain obscure. We investigated how the Golgi apparatus regulates glycosylation by studying biosynthesis of glycosphingolipids, glycosylated lipids with critical roles in signalling and differentiation. We identified the Golgi matrix protein GRASP55 as a controller of sphingolipid glycosylation by regulating the compartmentalized localization of key sphingolipid biosynthetic enzymes in the Golgi. GRASP55 controls the localization of the enzymes by binding to them and regulating their entry into peri-Golgi vesicles. Impairing GRASP55-enzyme interaction decompartmentalizes these enzymes, changes the substrate flux across competing glycosylation pathways that results in alteration of the cellular glycosphingolipid profile. This GRASP55 regulated pathway of enzyme compartmentalization allows cells to make cell density-dependent adaptations in glycosphingolipid biosynthesis to suit cell growth needs. Thus, the Golgi apparatus controls the cellular glycan (glycosphingolipid) profile by governing competition between biosynthetic reactions through regulated changes in enzyme compartmentalization.