Peter Linders, theme Cancer development and immune defence, Geert van den Bogaart, theme Nanomedicine, Dirk Lefeber, themes Metabolic disorders/Disorders of movement) together with international colleagues have recently reported on novel cell biological insights in Nature Communications. By identifying a genetic disorder in syntaxin-5 (STX5), they unraveled a new mechanism regulating intracellular transportation.
Congenital disorders of glycosylation (CDGs) form a group of neurometabolic diseases characterized by hypoglycosylation of proteins. A relatively novel class of CDGs involves abnormal intracellular trafficking of proteins, including the glycosylation machinery itself. With 5-10% of our genome dedicated to intracellular trafficking, the role of individual proteins in glycosylation and disease remains unsolved.
Syntaxin-5 is a so-called SNARE protein directly responsible for organelle trafficking between the endoplasmic reticulum and the Golgi apparatus. Syntaxin-5 therefore regulates how glycosylation machinery and products are transported, and indirectly affects glycosylation itself. Syntaxin-5 exists as two distinct isoforms (short and long) in humans, but the individual functions of these isoforms and how they are regulated is unknown.
Linders et al discovered patients with mutations in the second start codon, thereby fully disrupting the short isoform of STX5 while the long isoform could still be produced. Using cells derived from these patients, the authors showed a specific role for the short isoform STX5 in membrane trafficking at the Golgi apparatus and glycosylation. The researchers conclude that the precise regulation of expression of the short isoform of STX5 is paramount for physiological glycosylation.