Deficient glycan extension and endoplasmic reticulum stresses in ALG3-CDG.

Autor: Daniel EJP; Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA., Edmondson AC; Department of Pediatrics, Division of Genetics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA., Argon Y; Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA., Alsharhan H; Department of Pediatrics, College of Medicine, Kuwait University, Jabriya, Kuwait., Lam C; Division of Genetic Medicine, Department of Pediatrics, University of Washington School of Medicine, Seattle, Washington, USA., Freeze HH; Human Genetics Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA., He M; Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
Jazyk: angličtina
Zdroj: Journal of inherited metabolic disease [J Inherit Metab Dis] 2024 Jul; Vol. 47 (4), pp. 766-777. Date of Electronic Publication: 2024 Apr 10.
DOI: 10.1002/jimd.12739
Abstrakt: ALG3-CDG is a rare congenital disorder of glycosylation (CDG) with a clinical phenotype that includes neurological manifestations, transaminitis, and frequent infections. The ALG3 enzyme catalyzes the first step of endoplasmic reticulum (ER) luminal glycan extension by adding mannose from Dol-P-Man to Dol-PP-Man 5 GlcNAc 2 (Man5) forming Dol-PP-Man6. Such glycan extension is the first and fastest cellular response to ER stress, which is deficient in ALG3-CDG. In this study, we provide evidence that the unfolded protein response (UPR) and ER-associated degradation activities are increased in ALG3-CDG patient-derived cultured skin fibroblasts and there is constitutive activation of UPR mediated by the IRE1-α pathway. In addition, we show that N-linked Man3-4 glycans are increased in cellular glycoproteins and secreted plasma glycoproteins with hepatic or non-hepatic origin. We found that like other CDGs such as ALG1- or PMM2-CDG, in transferrin, the assembling intermediate Man5 in ALG3-CDG, are likely further processed into a distinct glycan, NeuAc 1 Gal 1 GlcNAc 1 Man 3 GlcNAc 2 , probably by Golgi mannosidases and glycosyltransferases. We predict it to be a mono-antennary glycan with the same molecular weight as the truncated glycan described in MGAT2-CDG. In summary, this study elucidates multiple previously unrecognized biochemical consequences of the glycan extension deficiency in ALG3-CDG which will have important implications in the pathogenesis of CDG.
(© 2024 SSIEM.)
Databáze: MEDLINE
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