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

Abstract

<jats:p>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.</jats:p>

Congenital disorder of glycosylation caused by starting site-specific variant in syntaxin-5

“…1e, Supplementary Table 2). ApoCIII-IEF showed a strong increase of non-sialylated apoCIII (ApoCIII-0) band intensities compared to the intensities of the fully glycosylated form, even stronger than observed for genetic defects in the Conserved Oligomeric Golgi (COG) complex, a known group of disorders with disturbed Golgi homeostasis and abnormal glycosylation 26 .…”

Congenital disorder of glycosylation caused by mutation of ATP6AP1 gene (c.1036G>A) in a Chinese infant: A case report

“…V-ATPase is a proton pump that transports H+ via active transport and provides a homeostatic pH environment for various cellular activities[ 5 ]. For example, maintaining the pH gradient from the cis to the trans Golgi apparatus ensures proper protein post-translational modifications and targeting[ 3 , 6 ]. V-ATPase of eukaryotes is widely distributed in the membranes of various subcellular organelles (such as Lysosomes, Golgi, clathrin-coated vesicles, platelet dense granules, and chromaffin granules) and on cell membranes[ 3 , 7 ].…”

The Close Relationship between the Golgi Trafficking Machinery and Protein Glycosylation

“…So far, more than 100 monogenic congenital disorders of glycosylation (CDGs) have been identified and associated with a wide variety of symptoms such as neurological deficit, liver disfunction, and skin and bone alterations [ 20 , 21 ]. Traditionally CDGs have been divided into two groups: CDG-I affect the synthesis and/or transfer of the dolichol pyrophosphate oligosaccharide precursor of N -linked glycoproteins, while CDG-II affect the processing of N -linked glycans or the biosynthesis of O- linked glycans [ 22 ].…”