Nucleotide-sugar transporter SLC35D1 is critical to chondroitin sulfate synthesis in cartilage and skeletal development in mouse and human

Hiraoka, Shûichi; Furuichi, Tatsuya; Nishimura, Gen; Shibata, Shunichi; Yanagishita, Masaki; Rimoin, David L.; Superti‐Furga, Andrea; Nikkels, Peter G. J.; Ogawa, Mamoru; Katsuyama, Kayoko; Toyoda, Hidenao; Kinoshita-Toyoda, Akiko; Ishida, Nobuhiro; Isono, Kyoichi; Sanai, Yutaka; Cohn, Daniel H.; Koseki, Haruhiko; Ikegawa, Shiro

doi:10.1038/nm1655

Cited by 102 publications

(107 citation statements)

References 22 publications

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“…NSTs result in various pathological phenotypes (4,20) [e.g., Schneckenbecken dysplasia in humans and mice resulting from mutations in a UDP-N-acetyl-α-D-galactosamine (GalNAc)/ UDP-GlcA transporter (21)]. Attempts to predict the function and substrate specificity of NSTs by protein sequence similarity have been unsuccessful (22); therefore, studies in other systems have provided minimal insight into predicting activity of the transporters in plants.…”

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confidence: 99%

The Golgi localized bifunctional UDP-rhamnose/UDP-galactose transporter family of Arabidopsis

Rautengarten

Ebert

Moreno

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

164

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Plant cells are surrounded by a cell wall that plays a key role in plant growth, structural integrity, and defense. The cell wall is a complex and diverse structure that is mainly composed of polysaccharides. The majority of noncellulosic cell wall polysaccharides are produced in the Golgi apparatus from nucleotide sugars that are predominantly synthesized in the cytosol. The transport of these nucleotide sugars from the cytosol into the Golgi lumen is a critical process for cell wall biosynthesis and is mediated by a family of nucleotide sugar transporters (NSTs). Numerous studies have sought to characterize substrate-specific transport by NSTs; however, the availability of certain substrates and a lack of robust methods have proven problematic. Consequently, we have developed a novel approach that combines reconstitution of NSTs into liposomes and the subsequent assessment of nucleotide sugar uptake by mass spectrometry. To address the limitation of substrate availability, we also developed a two-step reaction for the enzymatic synthesis of UDP-L-rhamnose (Rha) by expressing the two active domains of the Arabidopsis UDP-L-Rha synthase. The liposome approach and the newly synthesized substrates were used to analyze a clade of Arabidopsis NSTs, resulting in the identification and characterization of six bifunctional UDP-LRha/UDP-D-galactose (Gal) transporters (URGTs). Further analysis of loss-of-function and overexpression plants for two of these URGTs supported their roles in the transport of UDP-L-Rha and UDP-D-Gal for matrix polysaccharide biosynthesis. membrane transport | proteoliposomes | glycan biosynthesis | galactan

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mentioning

confidence: 99%

The Golgi localized bifunctional UDP-rhamnose/UDP-galactose transporter family of Arabidopsis

Rautengarten

Ebert

Moreno

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

164

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“…Diseases caused by mutations in these transporters affect humans (leukocyte adhesion deficiency syndrome II, LAD II 3 (1, 2) and Scheneckenbecken displasia (2,4,5)) and cattle (complex vertebral malformation (2,6)). Developmental phenotypes caused by mutations in nucleotide sugar transporters have been described in Drosophila (2,7), Caenorhabditis elegans (1, 2), Leishmania (1, 2, 8 -10), and yeast (1,2,11).…”

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confidence: 99%

Inhibition of Golgi Apparatus Glycosylation Causes Endoplasmic Reticulum Stress and Decreased Protein Synthesis

Liu

Caffaro³

et al. 2010

Journal of Biological Chemistry

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Nucleotide sugar transporters of the Golgi apparatus play an essential role in the glycosylation of proteins, lipids, and proteoglycans. Down-regulation of expression of the transporters for CMP-sialic acid, GDP-fucose, or both unexpectedly resulted in accumulation of glycoconjugates in the Golgi apparatus rather than in the plasma membrane. Pulse-chase experiments with radiolabeled sugars and amino acids showed decreased synthesis and secretion of both nonglycoproteins and glycoproteins. Further studies revealed that the above silencing induced endoplasmic reticulum stress and inhibited protein translation initiation. Together these results suggest that global inhibition of Golgi apparatus glycosylation may lead to important secondary metabolic changes, unrelated to glycosylation.

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“…These two nucleotide-activated sugars are involved in the biosynthesis of chondroitin sulfate, a main component of proteoglycans secreted by chondrocytes. Mutations in the SLC35D1 gene cause a skeletal disease called Schneckenbecken dysplasia, characterized by severe bone abnormalites leading to neonatal lethality [38]. It is likely that other classes of glycosylation are affected by the decreased transport of UDP-GlcA and UDP-GalNAc, but the extent of such alterations has not been addressed yet.…”

Section: Localization Of Donor Substratesmentioning

confidence: 99%

Congenital disorders of glycosylation: a concise chart of glycocalyx dysfunction

Hennet

Cabalzar

2015

Trends in Biochemical Sciences

108

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Glycosylation is a ubiquitous modification of lipids and proteins. Despite the essential contribution of glycoconjugates to the viability of all living organisms, diseases of glycosylation in humans have only been identified over the past few decades. The recent development of next-generation DNA sequencing techniques has accelerated the pace of discovery of novel glycosylation defects. The description of multiple mutations across glycosylation pathways not only revealed tremendous diversity in functional impairments, but also pointed to phenotypic similarities, emphasizing the interconnected flow of substrates underlying glycan assembly. The current list of 100 known glycosylation disorders provides an overview of the significance of glycosylation in human development and physiology. Congenital disorders of glycosylation -a consice chart of glycocalyx dysfunctionThierry Hennet, Jürg Cabalzar Institute of Physiology, University of Zurich, CH-8057 Zurich, Switzerland AbstractGlycosylation is a ubiquitous modification of lipids and proteins. Despite the essential contribution of glycoconjugates to the viability of all living organisms, diseases of glycosylation in humans have only been identified over the past few decades. The recent development of next-generation DNA sequencing techniques has accelerated the pace of discovery of novel glycosylation defects. The description of multiple mutations across glycosylation pathways has revealed a tremendous diversity of functional impairments bus also pointed to phenotypic similarities emphasizing the interconnected flow of substrates underlying glycan assembly. The current list of 100 known glycosylation disorders provides an overview on the significance of glycosylation in human development and physiology. Highlights Congenital disorders underline the role of glycosylation in human development.  Next-gen sequencing techniques expanded the discovery of glycosylation gene defects.  The clinical variability of glycosylation disorders implies they are underdiagnosed. Glycosylation disordersGlycosylation is by far the most complex form of protein [1,2] and lipid modification [3,4] in all domains of life. The tremendous diversity of glycoconjugate structures resulting from intricate biosynthetic pathways is a major factor hampering the assignment of functions to glycans chains. Much has been learnt from the study of disrupted glycosylation genes in model organisms, thereby establishing numerous essential contributions of glycans in regulating cell and organ functions [5]. The study of human diseases of glycosylation brings additional insights by providing a more differentiated view on glycan functions. Indeed, most human mutations are hypomorphic, thus causing partial loss of glycosylation reactions that lead to variable clinical manifestations.Diseases of glycosylation are also referred to as congenital disorders of glycosylation (CDG). Given the heterogeneity of glycans, the clinical scope of CDG is considerable, ranging from nearly normal phenotypes to sever...

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Nucleotide-sugar transporter SLC35D1 is critical to chondroitin sulfate synthesis in cartilage and skeletal development in mouse and human

Cited by 102 publications

References 22 publications

The Golgi localized bifunctional UDP-rhamnose/UDP-galactose transporter family of Arabidopsis

The Golgi localized bifunctional UDP-rhamnose/UDP-galactose transporter family of Arabidopsis

Inhibition of Golgi Apparatus Glycosylation Causes Endoplasmic Reticulum Stress and Decreased Protein Synthesis

Congenital disorders of glycosylation: a concise chart of glycocalyx dysfunction

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