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 the 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.

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GRASP55调节高尔基体中酶的区室化控制细胞糖鞘脂谱和功能

聚糖是细胞和机体生理的重要调节剂。这需要控制聚糖的生物合成以实现特定的细胞聚糖谱。聚糖在高尔基体中聚集在横穿其的分泌物上。高尔基体确保细胞和货物特异性糖基化的机制仍然不清楚。我们通过研究糖鞘脂，糖基化脂质在信号传导和分化中的关键作用的生物合成，研究了高尔基体如何调节糖基化。我们通过调节关键的鞘脂生物合成酶在高尔基体中的间隔化定位，确定了高尔基体基质蛋白GRASP55作为鞘脂糖基化的控制器。GRASP55通过与酶结合并调节其进入高尔基周囊泡的方式来控制酶的定位。削弱GRASP55-酶相互作用会使这些酶分解，改变竞争糖基化途径中的底物通量，从而导致细胞糖鞘脂谱的改变。这种由GRASP55调控的酶区分开途径使细胞能够在糖鞘脂生物合成中进行细胞密度依赖性的适应，以适应细胞生长的需要。因此，高尔基体装置通过调节酶区室化的变化来控制生物合成反应之间的竞争，从而控制细胞聚糖（糖鞘脂）的分布。改变竞争糖基化途径中的底物通量，导致细胞糖鞘脂谱的改变。这种由GRASP55调控的酶区分开途径使细胞能够在糖鞘脂生物合成中进行细胞密度依赖性的适应，以适应细胞生长的需要。因此，高尔基体装置通过调节酶区室化的变化来控制生物合成反应之间的竞争，从而控制细胞聚糖（糖鞘脂）的分布。改变竞争糖基化途径中的底物通量，导致细胞糖鞘脂谱的改变。这种由GRASP55调控的酶区分开途径使细胞能够在糖鞘脂生物合成中进行细胞密度依赖性的适应，以适应细胞生长的需要。因此，高尔基体装置通过调节酶区室化的变化来控制生物合成反应之间的竞争，从而控制细胞聚糖（糖鞘脂）的分布。