More than just sugars: Conserved oligomeric Golgi complex deficiency causes glycosylation‐independent cellular defects

• Published in: Traffic (Copenhagen, Denmark) Vol. 19; no. 6; pp. 463 - 480
• Main Authors: Blackburn, Jessica B., Kudlyk, Tetyana, Pokrovskaya, Irina, Lupashin, Vladimir V.
• Format: Journal Article
• Language: English
• Published: Former Munksgaard John Wiley & Sons A/S 01.06.2018; Wiley Subscription Services, Inc
• Subjects: Adaptor Proteins, Vesicular Transport - physiology; cathepsin D; CDG; Cell Line; COG complex; COG‐CDG; CRISPR; Defects; endolysosome; Epimerase; Fibroblasts; GALE; Glycosylation; Golgi; Golgi Apparatus - metabolism; Golgi cells; HEK293 Cells; Homeostasis; Humans; Lamp2; Membrane trafficking; MGAT1; Phenotype; Protein Transport - physiology; Secretion; Sugars - metabolism; Uridine; GALE; cathepsin D; Lamp2; endolysosome; CDG; COG complex; glycosylation; COG-CDG; Golgi; MGAT1
• ISSN: 1398-9219; 1600-0854
• DOI: 10.1111/tra.12564

The conserved oligomeric Golgi (COG) complex controls membrane trafficking and ensures Golgi homeostasis by orchestrating retrograde vesicle trafficking within the Golgi. Human COG defects lead to severe multisystemic diseases known as COG‐congenital disorders of glycosylation (COG‐CDG). To gain better understanding of COG‐CDGs, we compared COG knockout cells with cells deficient to 2 key enzymes, Alpha‐1,3‐mannosyl‐glycoprotein 2‐beta‐N‐acetylglucosaminyltransferase and uridine diphosphate‐glucose 4‐epimerase (GALE), which contribute to proper N‐ and O‐glycosylation. While all knockout cells share similar defects in glycosylation, these defects only account for a small fraction of observed COG knockout phenotypes. Glycosylation deficiencies were not associated with the fragmented Golgi, abnormal endolysosomes, defective sorting and secretion or delayed retrograde trafficking, indicating that these phenotypes are probably not due to hypoglycosylation, but to other specific interactions or roles of the COG complex. Importantly, these COG deficiency specific phenotypes were also apparent in COG7‐CDG patient fibroblasts, proving the human disease relevance of our CRISPR knockout findings. The knowledge gained from this study has important implications, both for understanding the physiological role of COG complex in Golgi homeostasis in eukaryotic cells, and for better understanding human diseases associated with COG/Golgi impairment. The conserved oligomeric Golgi (COG) complex controls membrane trafficking and Golgi homeostasis by orchestrating retrograde vesicle trafficking. COG deletions result in defects in glycosylation, trafficking and sorting as well as morphological abnormalities in the Golgi and endolysosomal compartments. A block in Golgi glycosylation does not recapitulate the majority of COG‐deficient phenotypes, indicating that these defects are due to interruption of specific roles of the COG complex independent of its role in the maintenance of Golgi glycosylation machinery.