Chemical Therapies for Congenital Disorders of Glycosylation

Sosicka, Paulina; Ng, Bobby G.; Freeze, Hudson H.

doi:10.1021/acschembio.1c00601

Cited by 15 publications

(4 citation statements)

References 69 publications

(153 reference statements)

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“…Congenital disorders of glycosylation (CDG) are rare in human populations, but there are many distinct diseases. At latest count, congenital mutations have been reported in >140 different genes involved in glycosylation (Sosicka et al, 2021;Lefeber et al, 2022). Of the glycosyltransferases that modify Notch EGF repeats and promote hematopoiesis, deleterious mutations compatible with life in humans have been identified in POFUT1, LFNG, and EOGT.…”

Section: Congenital Diseases Affected In Egf Repeat Modification By O...mentioning

confidence: 99%

Regulation of myeloid and lymphoid cell development by O-glycans on Notch

Stanley

Tanwar

2022

Front. Mol. Biosci.

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Notch signaling via NOTCH1 stimulated by Delta-like ligand 4 (DLL4) is required for the development of T cells in thymus, and NOTCH2 stimulated by Notch ligand DLL1 is required for the development of marginal zone (MZ) B cells in spleen. Notch signaling also regulates myeloid cell production in bone marrow and is an essential contributor to the generation of early hematopoietic stem cells (HSC). The differentiation program in each of these cellular contexts is optimized by the regulation of Notch signaling strength by O-glycans attached to epidermal growth factor-like (EGF) repeats in the extracellular domain of Notch receptors. There are three major types of O-glycan on NOTCH1 and NOTCH2 - O-fucose, O-glucose and O-GlcNAc. The initiating sugar of each O-glycan is added in the endoplasmic reticulum (ER) by glycosyltransferases POFUT1 (fucose), POGLUT1/2/3 (glucose) or EOGT (GlcNAc), respectively. Additional sugars are added in the Golgi compartment during passage through the secretory pathway to the plasma membrane. Of particular significance for Notch signaling is the addition of GlcNAc to O-fucose on an EGF repeat by the Fringe GlcNAc-transferases LFNG, MFNG or RFNG. Canonical Notch ligands (DLL1, DLL4, JAG1, JAG2) expressed in stromal cells bind to the extracellular domain of Notch receptors expressed in hematopoietic stem cells and myeloid and lymphoid progenitors to activate Notch signaling. Ligand-receptor binding is differentially regulated by the O-glycans on Notch. This review will summarize our understanding of the regulation of Notch signaling in myeloid and lymphoid cell development by specific O-glycans in mice with dysregulated expression of a particular glycosyltransferase and discuss how this may impact immune system development and malignancy in general, and in individuals with a congenital defect in the synthesis of the O-glycans attached to EGF repeats.

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Section: Congenital Diseases Affected In Egf Repeat Modification By O...mentioning

confidence: 99%

Regulation of myeloid and lymphoid cell development by O-glycans on Notch

Stanley

Tanwar

2022

Front. Mol. Biosci.

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“…In humans, defects in LLO synthesis or transfer to proteins cause inherited metabolic diseases known as congenital disorders of glycosylation (CDG) that manifest as a broad range of multisystem disorders or even embryonic lethality ( Jaeken, 2020 ; Pascoal et al, 2020 ). Based on recent statistical data, the number of identified ALG-CDGs is rapidly increasing, underscoring the significance of LLO synthesis to human disease ( Sosicka et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

An in vitro assay for enzymatic studies on human ALG13/14 heterodimeric UDP-N-acetylglucosamine transferase

Wang

Chen

et al. 2022

Front. Cell Dev. Biol.

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The second step of eukaryotic lipid-linked oligosaccharide (LLO) biosynthesis is catalyzed by the conserved ALG13/ALG14 heterodimeric UDP-N-acetylglucosamine transferase (GnTase). In humans, mutations in ALG13 or ALG14 lead to severe neurological disorders with a multisystem phenotype, known as ALG13/14-CDG (congenital disorders of glycosylation). How these mutations relate to disease is unknown because to date, a reliable GnTase assay for studying the ALG13/14 complex is lacking. Here we describe the development of a liquid chromatography/mass spectrometry-based quantitative GnTase assay using chemically synthesized GlcNAc-pyrophosphate-dolichol as the acceptor and purified human ALG13/14 dimeric enzyme. This assay enabled us to demonstrate that in contrast to the literature, only the shorter human ALG13 isoform 2, but not the longer isoform 1 forms a functional complex with ALG14 that participates in LLO synthesis. The longer ALG13 isoform 1 does not form a complex with ALG14 and therefore lacks GnTase activity. Importantly, we further established a quantitative assay for GnTase activities of ALG13- and ALG14-CDG variant alleles, demonstrating that GnTase deficiency is the cause of ALG13/14-CDG phenotypes.

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“…The transfer of various sugar residues to the hydroxy oxygen atom of serine, threonine, tyrosine, hydroxylysine, or hydroxyproline residues is known as O-linked glycosylation and occurs in the Golgi. Evidence demonstrates that both types of glycosylation are observed in proteins of epididymal fluid and are associated with spermatozoa (9,10). However, little is known about the role of protein glycosylation potentially in mink seasonal spermatogenesis.…”

Section: Introductionmentioning

confidence: 99%

Involvement of testicular N-glycoproteome heterogeneity in seasonal spermatogenesis of the American mink (Neovison vison)

Zhang

2022

Front. Vet. Sci.

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Spermatogenesis in the American mink is characterized by an annual cycle of transition involving completely inactive and fully activated stages. N-glycosylation of proteins has emerged as an important regulator as it affects protein folding, secretion, degradation, and activity. However, the function of protein N-glycosylation in seasonal spermatogenesis of the American mink remains unclear. In the present study, we established a proteome-wide stoichiometry of N-glycosylation in mink testes at various phases of spermatogenesis using N-linked glycosylated-peptide enrichment in combination with liquid chromatography-tandem mass spectrometry analysis. A total of 532 N-glycosylated sites matching the canonical Asn-X-Ser/Thr motif were identified in 357 testicular proteins. Both the number of glycoproteins and the sites of N-glycosylated proteins in mink testes were highly dynamic at different stages. Functional analyses showed that testicular proteins with different N-glycosylation might play a vital role in spermatogenesis by affecting their folding, distribution, stability, and activity. Overall, our data suggest that the dynamics of N-glycosylation of testicular proteins are involved in seasonal spermatogenesis in the American mink.

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Chemical Therapies for Congenital Disorders of Glycosylation

Cited by 15 publications

References 69 publications

Regulation of myeloid and lymphoid cell development by O-glycans on Notch

Regulation of myeloid and lymphoid cell development by O-glycans on Notch

An in vitro assay for enzymatic studies on human ALG13/14 heterodimeric UDP-N-acetylglucosamine transferase

Involvement of testicular N-glycoproteome heterogeneity in seasonal spermatogenesis of the American mink (Neovison vison)

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