Impact of Hypermannosylation on the Structure and Functionality of the ER and the Golgi Complex

• Published in: Biomedicines Vol. 11; no. 1; p. 146
• Main Authors: Franzka, Patricia, Schüler, Svenja Caren, Kentache, Takfarinas, Storm, Robert, Bock, Andrea, Katona, Istvan, Weis, Joachim, Buder, Katrin, Kaether, Christoph, Hübner, Christian A
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 06.01.2023; MDPI
• Subjects: Achalasia; Antibodies; Cytoskeleton; Dystroglycan; Endoplasmic reticulum; Experiments; Extracellular matrix; Furin; GDP-mannose; GDP-mannose pyrophosphorylase; Glycosylation; Golgi apparatus; Golgi network; Guanosine diphosphate; Homeostasis; Intellectual disabilities; Localization; Mannose; mannosylation; Membranes; Mutation; Proteins; Tears; United Kingdom > UK; Germany; mannosylation; Golgi network; endoplasmic reticulum
• ISSN: 2227-9059; 2227-9059
• DOI: 10.3390/biomedicines11010146

Proteins of the secretory pathway undergo glycosylation in the endoplasmic reticulum (ER) and the Golgi apparatus. Altered protein glycosylation can manifest in serious, sometimes fatal malfunctions. We recently showed that mutations in GDP-mannose pyrophosphorylase A (GMPPA) can cause a syndrome characterized by alacrima, achalasia, mental retardation, and myopathic alterations (AAMR syndrome). GMPPA acts as a feedback inhibitor of GDP-mannose pyrophosphorylase B (GMPPB), which provides GDP-mannose as a substrate for protein glycosylation. Loss of GMPPA thus enhances the incorporation of mannose into glycochains of various proteins, including α-dystroglycan (α-DG), a protein that links the extracellular matrix with the cytoskeleton. Here, we further characterized the consequences of loss of GMPPA for the secretory pathway. This includes a fragmentation of the Golgi apparatus, which comes along with a regulation of the abundance of several ER- and Golgi-resident proteins. We further show that the activity of the Golgi-associated endoprotease furin is reduced. Moreover, the fraction of α-DG, which is retained in the ER, is increased. Notably, WT cells cultured at a high mannose concentration display similar changes with increased retention of α-DG, altered structure of the Golgi apparatus, and a decrease in furin activity. In summary, our data underline the importance of a balanced mannose homeostasis for the secretory pathway.