Sugary Logistics Gone Wrong: Membrane Trafficking and Congenital Disorders of Glycosylation

Abstract

Glycosylation is an important post-translational modification for both intracellular and secreted proteins. For glycosylation to occur, cargo must be transported after synthesis through the different compartments of the Golgi apparatus where distinct monosaccharides are sequentially bound and trimmed, resulting in increasingly complex branched glycan structures. Of utmost importance for this process is the intraorganellar environment of the Golgi. Each Golgi compartment has a distinct pH, which is maintained by the vacuolar H⁺-ATPase (V-ATPase). Moreover, tethering factors such as Golgins and the conserved oligomeric Golgi (COG) complex, in concert with coatomer (COPI) and soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE)-mediated membrane fusion, efficiently deliver glycosylation enzymes to the right Golgi compartment. Together, these factors maintain intra-Golgi trafficking of proteins involved in glycosylation and thereby enable proper glycosylation. However, pathogenic mutations in these factors can cause defective glycosylation and lead to diseases with a wide variety of symptoms such as liver dysfunction and skin and bone disorders. Collectively, this group of disorders is known as congenital disorders of glycosylation (CDG). Recent technological advances have enabled the robust identification of novel CDGs related to membrane trafficking components. In this review, we highlight differences and similarities between membrane trafficking-related CDGs.

Keywords: Golgi apparatus; congenital disorders of glycosylation; glycosylation; membrane trafficking; post-translational modification; secretory pathway.

Figure 1

Schematic overview of the early secretory pathway in mammalian cells. Abbreviations: ER, endoplasmic reticulum; ERGIC, endoplasmic reticulum-Golgi intermediate compartment; COG complex, conserved oligomeric Golgi complex; COPI, coat protein complex I.

Figure 2

Schematic overview of the mammalian V-ATPase and the putative model of its assembly. Lowercase letters denote the various subunits of the V₀-domain; uppercase letters denote the subunits of the V₁-domain. The assembly factors VMA21, TMEM199, and CCDC115 might assemble the membrane-associated V₀-domain of the V-ATPase. VMA21 interacts with V₀c’ and V₀a [79,80,81,82], TMEM199 and CCDC115 interact with V₀a [83]. Abbreviations: V-ATPase, vacuolar H⁺-ATPase; CDG, congenital disorder of glycosylation.

Figure 3

Schematic overview of COPI vesicle capture by coiled-coil tethering proteins at the Golgi. Tentacular coiled-coil proteins attached to the Golgi membrane can capture COPI vesicles to direct them to the Golgi. Abbreviations: CDG, congenital disorder of glycosylation; COG complex, conserved oligomeric Golgi complex; COPI, coat protein complex I; SNARE, soluble N-ethylmaleimide-sensitive factor attachment protein receptor.

Figure 4

Schematic overview of COG-mediated vesicle tethering and SNARE-mediated vesicle fusion at the Golgi. COPI vesicles are tethered to the Golgi membrane through the interaction of COG lobes A and B. Subsequently, SNARE-mediated membrane fusion occurs, and the vesicle cargo is released to the Golgi lumen. Abbreviations: CDG, congenital disorder of glycosylation; COG complex, conserved oligomeric Golgi complex; COPI, coat protein I; SNARE, soluble N-ethylmaleimide-sensitive factor attachment protein receptor.