No abstract

The Golgi apparatus, the main glycosylation station of the cell, consists of a stack of discontinuous cisternae. Glycosylation enzymes are usually concentrated in one or two specific cisternae along the cis‐trans axis of the organelle. How such compartmentalized localization of enzymes is achieved and how it contributes to glycosylation are not clear. Here, we show that the Golgi matrix protein GRASP55 directs the compartmentalized localization of key enzymes involved in glycosphingolipid (GSL) biosynthesis. GRASP55 binds to these enzymes and prevents their entry into COPI‐based retrograde transport vesicles, thus concentrating them in the trans‐Golgi. In genome‐edited cells lacking GRASP55, or in cells expressing mutant enzymes without GRASP55 binding sites, these enzymes relocate to the cis‐Golgi, which affects glycosphingolipid biosynthesis by changing flux across metabolic branch points. These findings reveal a mechanism by which a matrix protein regulates polarized localization of glycosylation enzymes in the Golgi and controls competition in glycan biosynthesis.

No abstract

Two decades ago, we achieved molecular cloning of ganglioside GM3 synthase (GM3S; ST3GAL5), the enzyme responsible for initiating biosynthesis of complex gangliosides. The efforts of our research group since then have been focused on clarifying the physiological and pathological roles of gangliosides, particularly GM3. This review summarizes our long-term studies on the roles of GM3 in insulin resistance and adipogenesis in adipose tissues, cholesterol uptake in intestine, and leptin resistance in hypothalamus. We hypothesized that GM3 plays a role in innate immune function of macrophages, and demonstrated that molecular species of GM3 with Accepted ArticleThis article is protected by copyright. All rights reserved differing acyl-chain structures and modifications functioned as pro-and anti-inflammatory endogenous Toll-like receptor 4 (TLR4) modulators in macrophages. Very-long-chain and α-hydroxy GM3 species enhanced TLR4 activation, whereas long-chain and unsaturated GM3 species counteracted this effect. Lipidomic analyses of serum and adipose tissues revealed that imbalances between such pro-and anti-inflammatory GM3 species promoted progression of metabolic disorders. GM3 thus functions as a physiological regulatory factor controlling the balance between homeostatic and pathological states.Ongoing studies based on these findings will clarify the mechanisms underlying ganglioside-dependent control of energy homeostasis and innate immune responses.