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Matheny-Rabun C, Mokashi SS, Radenkovic S, Wiggins K, Dukes-Rimsky L, Angel P, Ghesquiere B, Kozicz T, Steet R, Morava E, Flanagan-Steet H. O-GlcNAcylation modulates expression and abundance of N-glycosylation machinery in an inherited glycosylation disorder. Cell reports 2024 43(11) 39561044
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.
O-GlcNAc proteins:
A2BFS6, NGBR
Species: Danio rerio
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