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Biochimica et Biophysica Acta 1792 (2009) 921–924

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Biochimica et Biophysica Acta

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Review From glycosylation disorders back to glycosylation: What have we learned?

Thierry Hennet

Institute of Physiology, University of Zürich, Switzerland

article info abstract

Article history: Diseases of glycosylation have long remained confined to the rare hematological disorders, the Tn-syndrome Received 29 August 2008 [1] and paroxysmal nocturnal hemoglobinuria ,[2]. This rarity was often interpreted as a sign that defects of Accepted 9 October 2008 glycosylation are either lethal, or remain asymptomatic because of the large redundancy found in Available online 22 October 2008 glycosylation pathways. The description of multiple glycosylation disorders over the last years has definitively settled the issue and demonstrated the broad range of biological processes relying on proper Keywords: Dystroglycan glycosylation. However, beyond establishing the developmental and physiological roles of glycosylation how fi Mucin O-glycosylation did glycosylation disorders provided new insights to the eld of glycobiology? Oligosaccharyltransferase © 2008 Elsevier B.V. All rights reserved. COG complex CMP-sialic acid

Diseases presenting similar clinical features often share common glycosylation. Whereas O-linked mannosylated glycans had been causes. Such phenotypic similarities have helped expanding the inventory documented in multicellular organisms including mammals [3],the of involved in common glycosylation pathways. This was the case structure of the O-mannosylated chains and the nature of the dedicated for various forms of congenital muscular dystrophies, which allowed have long remained unclear. The description of the associating putative genes with α-dystroglycan POMGNT1 glycosyltransferase and its association to Muscle–Eye–Brain glycosylation. In other instances, similar clinical features pointed to disease [4] rapidly brought O-mannosylation to the central stage of relationships between glycosyltransferases and their protein substrates. congenital muscular dystrophies. The successive description of FKRT [5], Typically, the identification of the polypeptide GalNAc--3 POMT1 [6],POMT2[7],LARGE[8] and the reinterpretation of the fukutin mutations as a cause of tumor calcinosis shed new light on the significance defect [9] definitively established the importance of α-dystroglycan of O-GalNac modifications in the context of FGF23 functions. Furthermore, glycosylation in the etiology of congenital muscular dystrophies. the identification of glycosylation disorders linked to defects of vesicular Whereas the involvement of the aforementioned proteins in α- transport has advanced the understanding of the mechanisms involved in dystroglycan glycosylation is undisputed, to date only POMT and glycosyltransferase localization. Sometimes, the description of novel POMGNT1 have been assigned a clear glycosyltransferase activity. glycosylation disorders yielded unexpected findings, which raised new LARGE, fukutin and FKRP show structural features typical of glycosyl- questions on the functions of previously described genes. For example, but their enzymatic activities remain unknown. Studies mutations in the UDP-GlcNAc-2-epimerase/N-acetylmannosamine performed in mutant CHO cells have shown that LARGE is capable of kinase caused a relatively mild myopathy, which was strongly in elongating both O-and N-glycan chains [10]. The presence of two distinct contrast to the embryonic lethality observed in the corresponding glucosyltransferase- and N-acetylglucosaminyltransferase-like domains knockout mouse model. In conclusion, glycosylation disorders can reveal in LARGE suggests that this protein may have a carbohydrate interesting features of glycoconjugates or open new perspectives on polymerizing activity as observed in the biosynthesis of glycosamino- specificpathways. glycan chains [11,12]. The large carbohydrate moiety of the α- dystroglycan protein certainly supports this notion. So why have the 1. Dystroglycan glycosylation activity of LARGE, fukutin and FKRP remained intractable in spite of numerous efforts? Like for other orphan glycosyltransferases, several The description of several glycosylation disorders among the family options could account for the missing activity. It could be that these of congenital muscular dystrophies certainly expanded the visibility require a co-factor that has not been identified yet. Alterna- and biological significance of the O-mannosylation pathway. Protein tively, it is possible that these enzymes build heteromeric complexes O-mannosylation was long considered to be specific to fungal cell wall with partners that have not been considered yet. It could also be that these enzymes transfer carbohydrates to acceptor substrates modified by sulfation or phosphorylation as it has been described for the formation of E-mail address: [email protected]. the glycosaminoglycan tetrasaccharide core [13]. Although the puzzle of

0925-4439/$ – see front matter © 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.bbadis.2008.10.006 922 T. Hennet / Biochimica et Biophysica Acta 1792 (2009) 921–924

α-dystroglycan biology is not complete, the description of glycosylation mental retardation has also been related to mutations in the CRBN, defects in congenital muscular dystrophies has allowed grouping some CC2D1A, PRSS12 and GRIK2 genes. The latter gene encodes a subunit of pieces, i.e. putative glycosyltransferases, around the central figure of α- the glutamate receptor, which carries eight N-glycosylation sites. The dystroglycan. phenotypic similarity between the OST3 and GRIK2 defects may indicate that OST3 is required for GRIK2 expression or activity. 2. Mucin O-glycosylation Although representing a difficult task, the description of the OST3 deficiency prompted for the search of specifically underglycosylated Mucin-type O-glycosylation is initiated by the transfer of α-linked proteins. The characterization of OST3 substrate specificity would GalNAc to the hydroxyl group of serine and threonine. This step is contribute to a better understanding of the mechanisms underlying catalyzed by a family of polypeptide GalNAc-transferases comprising at the recognition of glycosylation substrates during protein translation. least 20 members [14]. This multitude of isoforms makes it challenging to predict the outcome of single defects. Therefore, the association of 4. LLO the polypeptide GalNAc-transferase-3 GALNT3 gene with a form of tumoral calcinosis [15] came as a surprise. Tumoral calcinosis, a disorder The comparison of the clinical features linked to different defects of calcium and phosphate metabolism, is also caused by mutations in the of LLO assembly pointed to a peculiar observation. The last steps of FGF23 [16] and KLOTHO [17] genes. The discovery of the GALNT3 defect as a LLO assembly are catalyzed by the ALG6, ALG8 and ALG10 glucosyl- cause of tumoral calcinosis demonstrated the role of O-glycosylation transferases (Fig. 1). Whereas ALG6 and ALG8 defects lead to the in the secretion and functions of the FGF23 glycoprotein. In fact, FGF23 is accumulation of very similar LLO structures, the clinical outcome of O-glycosylated and it has been shown that a specific O-glycan chain ALG8 deficiency is more severe than that of ALG6 deficiency. The main protects the FGF23 protein from cleavage by subtilisin-like proteases while features associated to ALG6 deficiency, which causes CDG-Ic [25], are transiting through the secretory pathway [18]. This case is not unique since central hypotonia and mild coagulopathy [26]. By contrast, ALG8 O-glycosylation has also been shown to protect the intracellular deficiency, which causes CDG-Ih [27,28], leads to cardio-respiratory proteolytic cleavage of the endopeptidase meprin [19] and to be required problems, dysmorphism, oedema in addition to a central hypotonia for the expression of the LDL receptor [20]. Additional examples are likely and coagulopathy as found in CDG-Ic. Most ALG8 patients died in their to follow, thereby drawing functional relationships between O-glycosyl- infancy, with one exception presenting a mild clinical outcome [28]. transferases and specific glycoproteins. So far, the GALNT3 defect What are the reasons for the clinical discrepancy between the ALG6 contributes to establish the importance of O-glycosylation for the and ALG8 deficiencies? It is possible that the mutations found in the intracellular processing of glycoproteins. ALG8 gene lead to a stronger underglycosylation than found in ALG6 deficiency. However, the comparison of the level of transferrin 3. Oligosaccharyltransferase glycosylation between ALG6 and ALG8 deficiency does not support this hypothesis. Alternatively, the different clinical outcome may be Several disorders of N-glycosylation have been characterized in the related to different functions of the ALG6 and ALG8 glucosyltrans- last decade, largely thank to the easy detection of abnormally ferases. The characterization of the ALG8 deficient fibroblasts revealed glycosylated serum transferrin by isoelectric focusing. Abnormal an unexpected glucosidase activity targeting LLOs. Indeed, ALG8 transferrin glycosylation was observed for defects of lipid-linked deficiency was accompanied by the accumulation of the incomplete oligosaccharide (LLO) assembly and for defects of N-glycan proces- LLOs dolichyl-pyrophosphate-GlcNAc2Man9 and -GlcNAc2Man9Glc1 sing. Even defects of glycosyltransferase localization, such as encoun- [27,28], whereas only the latter structure was expected to accumulate. tered in COG deficiency, affect the N-glycosylation of transferrin. This presence of the LLO dolichyl-pyrophosphate-GlcNAc2Man9 in Whereas most genes of the N-glycosylation pathway encoding ER- ALG8-deficient cells indicated that glucosylated LLOs are substrates of localized proteins have been related to glycosylation disorders, the the glucosidase-II enzyme, which removes Glc residues on N-glycans oligosaccharyltransferase complex has remained a lonely exception. after they have been transferred to proteins [29]. The accumulation of This multiprotein complex is expressed ubiquitously and it was incomplete glucosylated LLOs in the ALG8-deficient cells may divert or expected that defective oligosaccharyltransferase activity would impair glucosidase-II activity and thereby worsen the impact of the result in abnormal transferrin glycosylation. However, the recently ALG8 defect itself on protein glycosylation, folding and secretion. described mutations in the TUSC3/N33 gene [21,22], which encodes Although the involvement of glucosidase-II in the pathogenesis of the oligosaccharyltransferase subunit OST3, did not affect the N- CDG-Ih is hypothetical at this stage, the question of the distinct glycosylation of transferrin. The OST3 protein is homologous to the severity between ALG6 and ALG8 deficiency shows how the study of OST6 subunit and analyses conducted in yeast have shown that OST3 glycosylation disorders lead to new questions and thereby to new and OST6 form distinct complexes with the other oligosaccharyl- concepts on the mechanisms underlying protein glycosylation. transferase subunits [23]. OST3 and OST6 are functionally related since OST3 deficiency can be partially rescued by OST6 and vice versa [24]. This functional overlap explains why the deletion of the OST3 gene in yeast yielded only minor N-glycosylation defects. Along this line, the normal glycosylation of serum transferrin detected in human OST3 deficiency may be related to such a redundancy between OST3 and OST6. Despite the partial interchangeability of OST3 and OST6, the association of OST3 mutations with nonsyndromic mental retardation [21,22] demonstrated the unique contribution of OST3 towards specific glycoproteins. At the biomedical level, two lessons can be learned from this result. Firstly, the normal N-glycosylation of serum transferrin seen in OST3 deficiency suggests that additional glycosyla- tion disorders have certainly remained undiagnosed to date and that Fig. 1. Glucosylation and deglucosylation of lipid-linked oligosaccharides in the other tests should be developed to detect potential restricted endoplasmic reticulum. The ALG6, ALG8 and ALG10 glucosyltransferases add each a Glc residue to the dolichol-pyrophosphate-GlcNAc Man oligosaccharide. The char- glycosylation defects. Secondly, the mental retardation phenotype 2 9 acterization of CDG-Ih has demonstrated that the glucosidase-II (GLS2) enzyme is indicated that OST3 is required for the proper glycosylation and capable of deglucosylating LLOs. A similar activity of the glucosidase-I (GLS1) enzyme functions of proteins in the central nervous system. Nonsyndromic on LLOs has not been shown yet. T. Hennet / Biochimica et Biophysica Acta 1792 (2009) 921–924 923

5. Glycosyltransferase localization glycosylation disorders. This work was supported by a grant from the Swiss National Science Foundation (3100A0-116039) and by the The localization of glycosyltransferases is a dynamic process tightly European Union project Euroglycanet (LSHM-2005-512131). regulated with the flow of secreted proteins. Recently, defects of glycosylation have been related to the abnormal assembly of the Conserved Oligomeric Golgi (COG) complex, which is a tethering References complex involved in vesicular transport. The COG complex is found in [1] E.G. Berger, Tn-syndrome, Biochim. Biophys. Acta 1455 (1999) 255–268. eukaryotes from yeast up to human cells. Although the cellular [2] L. Luzzatto, M. Bessler, B. Rotoli, Somatic mutations in paroxysmal nocturnal functions of COG are still being established, the discovery of COG hemoglobinuria: a blessing in disguise? Cell 88 (1997) 1–4. defects among glycosylation disorders demonstrated the importance [3] J. Finne, T. 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