PUBLICATION
O-GlcNAcylation modulates expression and abundance of N-glycosylation machinery in an inherited glycosylation disorder
- Authors
- Matheny-Rabun, C., Mokashi, S.S., Radenkovic, S., Wiggins, K., Dukes-Rimsky, L., Angel, P., Ghesquiere, B., Kozicz, T., Steet, R., Morava, E., Flanagan-Steet, H.
- ID
- ZDB-PUB-241120-3
- Date
- 2024
- Source
- Cell Reports 43: 114976114976 (Journal)
- Registered Authors
- Flanagan-Steet, Heather, Steet, Richard, Wiggins, Kali
- Keywords
- CDG, CP: Molecular biology, O-GlcNAc, disease modifiers, glycosylation, sugar metabolism, zebrafish
- Datasets
- GEO:GSE269074
- MeSH Terms
-
- Acetylglucosamine/metabolism
- Protein Processing, Post-Translational
- Humans
- Phosphotransferases (Phosphomutases)*/genetics
- Phosphotransferases (Phosphomutases)*/metabolism
- Animals
- Glycosylation
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism
- Mutation/genetics
- Congenital Disorders of Glycosylation*/genetics
- Congenital Disorders of Glycosylation*/metabolism
- Congenital Disorders of Glycosylation*/pathology
- Zebrafish*/metabolism
- PubMed
- 39561044 Full text @ Cell Rep.
Citation
Matheny-Rabun, C., Mokashi, S.S., Radenkovic, S., Wiggins, K., Dukes-Rimsky, L., Angel, P., Ghesquiere, B., Kozicz, T., Steet, R., Morava, E., Flanagan-Steet, H. (2024) O-GlcNAcylation modulates expression and abundance of N-glycosylation machinery in an inherited glycosylation disorder. Cell Reports. 43:114976114976.
Abstract
Core components of the N-glycosylation pathway are known, but the metabolic and post-translational mechanisms regulating this pathway in normal and disease states remain elusive. Using a multi-omic approach in zebrafish, we discovered a mechanism whereby O-GlcNAcylation directly impacts the expression and abundance of two rate-limiting proteins in the N-linked glycosylation pathway. We show in a model of an inherited glycosylation disorder PMM2-CDG, congenital disorders of glycosylation that phosphomannomutase deficiency is associated with increased levels of UDP-GlcNAc and protein O-GlcNAcylation. O-GlcNAc modification increases the transcript and protein abundance of both NgBR and Dpagt1 in pmm2m/m mutants. Modulating O-GlcNAc levels, NgBR abundance, or Dpagt1 activity exacerbated the cartilage phenotypes in pmm2 mutants, suggesting that O-GlcNAc-mediated increases in the N-glycosylation machinery are protective. These findings highlight nucleotide-sugar donors as metabolic sensors that regulate two spatially separated glycosylation pathways, demonstrating how their coordination is relevant to disease severity in the most common congenital disorder of glycosylation.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping