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The O-Mannosylation Pathway: Glycosyltransferases and Proteins Implicated in Congenital Muscular Dystrophy *

The O-Mannosylation Pathway: Glycosyltransferases and Proteins Implicated in Congenital Muscular... MINIREVIEW THE JOURNAL OF BIOLOGICAL CHEMISTRY VOL. 288, NO. 10, pp. 6930 –6935, March 8, 2013 © 2013 by The American Society for Biochemistry and Molecular Biology, Inc. Published in the U.S.A. the plasma membrane, most notably dystroglycan (18). Dystro- The O-Mannosylation Pathway: glycan is a single gene product (DAG1) that is processed into Glycosyltransferases and two subunits: -dystroglycan, that is a transmembrane protein that interacts with dystrophin in the cytoplasm, and -dystro- Proteins Implicated in glycan, which is a soluble secreted glycoprotein that interacts Congenital Muscular Dystrophy with both -dystroglycan and multiple components of the Published, JBC Papers in Press, January 17, 2013, DOI 10.1074/jbc.R112.438978 extracellular matrix, such as laminin, perlecan, pikachurin, Lance Wells neurexin, and agrin (18–23). These extracellular matrix pro- From the Complex Carbohydrate Research Center and Department of teins recognize and bind the unusual glycan structures on Biochemistry and Molecular Biology, University of Georgia, -dystroglycan. Thus, proper glycosylation of -dystroglycan is Athens, Georgia 30602 essential for binding to extracellular matrix components (24). Although -dystroglycan is both N- and O-linked glycosylated, Several forms of congenital muscular dystrophy, referred to as it is the O-linked glycans that are essential for proper function dystroglycanopathies, result from defects in the proteinO-man- (25). In terms of O-linked glycosylation, -dystroglycan con- nosylation biosynthetic pathway. In this minireview, I discuss 12 tains both classical mucin-like O-GalNAc-initiated glycans and proteins involved in the pathway and how they play a role in the the more unusual O-Man-initiated glycans (11). Multiple stud- building of glycan structures (most notably on the protein ies have clearly demonstrated that it is the O-mannosylated -dystroglycan) that allow for binding to multiple proteins of glycan structures that serve as binding sites for laminin and the extracellular matrix. presumably other extracellular matrix proteins (18–23). Inter- estingly, it appears to be these same essential structures that are recognized by the antibody IIH6 and that are used as cellular Although O-mannosylation of mammalian proteins was binding sites by some arenaviruses (9, 26). observed almost 35 years ago (1), it was not until the turn of the The initial O-mannose residue is added to serines and thre- millennium that the importance of this protein post-transla- onines of -dystroglycan and other proteins that have not been tional modification pathway began to be appreciated. In the clearly defined but certainly must exist in the endoplasmic early 2000s, multiple groups established that deficiencies of reticulum (ER) (27, 28). Multiple sites of O-mannosylation (and enzymes in this pathway result in multiple forms of congenital O-GalNAcylation) on -dystroglycan have been established (8, muscular dystrophy (CMD) that have now been termed dys- 11, 12). This O-mannose can then be extended to create a troglycanopathies (2–6). Recent work has begun to unravel the variety of glycan structures (Fig. 1) (reviewed recently in structures of the functional glycans that are altered and to iden- Refs. 13 and 29). In terms of how O-mannose-extended gly- tify sites of modification on -dystroglycan (7–12), the most can structures are important for binding to the extracellular well characterized and clearly functionally relevant O-manno- matrix, two recent studies have made substantial contributions sylated protein (13, 14). While briefly describing the dystro- (7, 10). It has been demonstrated on -dystroglycan that a phin-dystroglycan complex and the diversity of O-mannosy- GalNAc-3-GlcNAc-4-Man structure that is phosphorylated lated structures, this minireview will primarily highlight the at the 6-position of mannose and further extended by an enzymes and proteins that are known to be defective in unknown moiety on the distal side of the phosphate, forming a dystroglycanopathies. phosphodiester structure, is essential for binding to extracellu- Several forms of muscular dystrophy result at least in part lar matrix proteins (10). Most recently, it has been proposed from defects in the dystrophin-glycoprotein complex (15, 16). that a key component of this unknown extension from the This complex serves to link the actin cytoskeleton to the extra- phosphate contains the repeating disaccharide -3-GlcUA-3- cellular matrix via a complex of cytosolic proteins and plasma Xyl- (7). membrane-localized glycoproteins (17). Duchenne muscular Other recent reviews have focused on the structures, sub- dystrophy, which is the most common form of muscular dys- strates, and functional implications of the O-mannosylation trophy, is an X-linked recessive disorder resulting from loss of pathway and the phenotypes observed in the various muscular expression of functional dystrophin, a cytoplasmic actin-bind- dystrophies (13, 14, 17, 24, 29, 30). Here, I review the enzymes/ ing protein (16). Dystrophin is connected to a set of proteins at proteins of the pathway that have been implicated in CMD. * This work was supported, in whole or in part, by National Institutes of Health Enzymes/Proteins of the Pathway Grant P41RR018502 from NIGMS (to L. W., senior investigator). This work was also supported by the Georgia Research Alliance (to Lars G. Ljungdahl, Over the last decade, a variety of enzymes and proteins have investigator, and L. W.). This is the fourth article in the Thematic Minireview been implicated in the O-mannosylation pathway. Here, I focus Series on Glycobiology and Extracellular Matrices: Glycan Functions Per- primarily on the human proteins involved in the pathway that, vade Biology at All Levels. To whom correspondence should be addressed. E-mail: lwells@ccrc. when defective, have been shown to cause CMD, specifically uga.edu. dystroglycanopathies (Table 1). It should be noted that at least The abbreviations used are: CMD, congenital muscular dystrophy; ER, endo- one-third of dystroglycanopathies are of unknown genetic eti- plasmic reticulum; GlcUA, glucuronic acid; DPM, dolichol-phosphate man- nose; CDG, congenital disorders of glycosylation; GnT, GlcNAc-transferase. ology and do not have defects in the known gene products 6930 JOURNAL OF BIOLOGICAL CHEMISTRY VOLUME 288 • NUMBER 10 •MARCH 8, 2013 This is an Open Access article under the CC BY license. MINIREVIEW: O-Mannosylation and CMD Dolichyl-phosphate-mannose:Protein Mannosyltransferase (POMT1/2)—Initial O-mannosylation of proteins in the ER is catalyzed by POMT1/2 using DPM as the donor (39, 40). POMT1 and POMT2 belong to the inverting GT39 family in the CAZy Database. The proper expression of both proteins together is required for the catalysis of this first step in the O-mannosylation pathway (40, 41). Multiple mutations in both genes are causal for CMD, and complete loss-of-function muta- tions cause Walker-Warburg syndrome, the most severe of the dystroglycanopathies (42–49). Localization of these enzymes in the ER infers that O-mannosylation precedes classical mucin-like O-GalNAcylation of proteins in the secretory path- way. A recent study has demonstrated that O-mannosylation appears to modulate O-GalNAc addition and site selection (50). FIGURE 1. O-Mannose structures. O-Man-initiated glycans can be elabo- rated into linear or branched structures. A key structure for binding to extra- Furthermore, loss of O-mannosylation would potentially pro- cellular matrix proteins is not fully resolved but contains a phosphodiester vide novel sites for the polypeptide GalNAc transferases in the linkage, and a component of the X moiety is likely to be the LARGE-catalyzed cis-Golgi. Thus, loss of O-mannosylation may alter O-GalNAc repeating disaccharide. Green circles, Man; blue squares, GlcNAc; yellow square, GalNAc; yellow circles, Gal; pink diamonds, Neu5Ac; red triangles, Fuc; addition on proteins, and this “gain of modification” could be orange star, Xyl; blue/white diamond, GlcUA. GlcNAc residues on the O-Man responsible for some of the observed phenotypes in CMD. added in the 2-position are drawn up to the left, in the 4-position straight up, and in the 6-position up to the right. Asymmetric branched structures are 2-C-Methyl-D-Erythritol 4-Phosphate Cytidylyltransferase- drawn in only one possible configuration, although isomeric structures are like Protein (Isoprenoid Synthase Domain-containing (ISPD))— likely to exist. ISPD is not predicted to be a glycosyltransferase, yet mutations involved to date in the O-mannosylation pathway. Further- in this protein cause Walker-Warburg syndrome with clear loss more, several of the enzymes needed to build the array of struc- of -dystroglycan functional glycosylation (51, 52). This tures observed (Fig. 1) are common to multiple pathways, such enzyme has high similarity to an enzyme in the non-mevalonate as the sialyltransferases, fucosyltransferases, and galactosyl- pathway for isoprenoid synthesis (53). However, mammals are transferases, and are not discussed here, as there is no evidence thought to use only the mevalonate pathway, and several other to date for them being defective in CMD. Finally, O-mannosy- enzymes in the bacterial non-mevalonate pathway are not obvi- lation is an evolutionarily conserved post-translational modifi- ously conserved in higher animals (53). Thus, the role for this cation from yeast to man, and several model systems have pro- putative enzyme remains unclear, although it clearly impacts vided invaluable insights into the pathway (31–33). the ability of POMT1/2 to transfer O-mannose (52). Does the Dolichol-phosphate Mannose Synthase—Dolichol-phos- defect in ISPD affect other types of glycosylation that depend on phate mannose (DPM) is the donor for luminal ER mannosyla- dolichol-linked sugars? Does ISPD play a role in modification of tion, including N-, O-, and C-glycosylation as well as glycophos- dolichol-linked mannose? These questions have yet to be fully phatidylinositol anchor biosynthesis (34). DPM is synthesized explored. from GDP-Man and dolichol phosphate via an inverting mech- UDP-GlcNAc:O-Linked Mannose 1,2-N-Acetylglucosami- anism on the cytosolic side of the ER (34). This reaction is cat- nyltransferase (POMGnT1)—POMGnT1 catalyzes the exten- alyzed by the DPM synthase complex (34). The catalytic activity sion of the O-mannose-initiated structure with a GlcNAc in a is performed by DPM1, a dolichol-phosphate -D-mannosyl- 2-linkage and is a member of the CAZy GT13 family of invert- transferase belonging to the glycosyltransferase 2 (GT2) family ing enzymes (6). Mutations in this gene are observed in patients of the CAZy (Carbohydrate-Active enZYmes) Database (34). with multiple forms of dystroglycanopathy (6, 54–59). Mice DPM2 and DPM3 are ER-localized transmembrane proteins with a knock-out of this enzyme present with phenotypes con- that interact with the catalytic DPM1 protein to form a fully sistent with human muscle-eye-brain disease, a severe form of active DPM synthase complex (35). Causal mutations for a dys- CMD (55). Genotype-phenotype correlations have begun to be troglycanopathy phenotype along with type I congenital disor- established for this enzyme (54). This enzyme is localized in the ders of glycosylation (CDG) have been observed in DPM2 and cis-Golgi, and its action appears to be essential for not only DPM3 (36, 37). Although patient mutations in DPM1 cause a 2-extension but also 6-branching of the O-mannose moiety severe form of CDG (38), surprisingly, no dystroglycanopathy with GlcNAc (28). 6-Branching of the O-mannose is catalyzed or muscular dystrophy has been noted. Given the vital role of by UDP-GlcNAc:mannose 1,6-N-acetylglucosaminyltrans- DPM in multiple forms of glycosylation, it is perhaps not sur- ferase, GnT-Vb (GnT-IX) (60). Although GnT-Vb and O-man- prising that mutations in DPM2 and DPM3 cause severe pleio- nose branching is localized primarily to the brain, making the tropic phenotypes. Whether DPM2/3 mutations are truly gene an attractive potential affected target for undiagnosed causal for CMD remains controversial in the field. The proteins CMD with neurological complications, mice lacking GnT-Vb responsible for flipping the DPM to the lumen of the ER have alone or in combination with a knock-out of GnT-Va (which not been determined, and impairment of function of these pro- can partially compensate for O-Man branching in the absence teins would also likely lead to a plethora of complications of GnT-Vb) do not display any gross brain abnormalities or resembling both CMD and CDG, as observed for DPM2 and muscular dystrophy (61). Given the recent finding that the DPM3. 6-phosphomannose structure that was presumably extended MARCH 8, 2013• VOLUME 288 • NUMBER 10 JOURNAL OF BIOLOGICAL CHEMISTRY 6931 MINIREVIEW: O-Mannosylation and CMD TABLE 1 Enzymes/proteins involved in the O-mannosylation pathway and potentially CMD Gene Protein functions CAZy family DPM2 and DPM3 Facilitate DPM1-catalyzed formation of DPM GT2 (DPM1) POMT1 and POMT2 Protein O-Man transferase GT39 ISPD Unknown (putative enzyme) None POMGnT1 O-Man 2-GlcNAc transferase GT13 Fukutin and FKRP Unknown (LicD motif putative enzymes) None LARGE1 and LARGE2 Dual-activity glycosyltransferase: GlcUA 3-Xyl GT8/GT49 transferase and Xyl 3-GlcUA transferase GTDC2 Unknown (putative glycosyltransferase) GT61 with the functional glycan that is LARGE-dependent had an Xyl-, as each product of one domain is a substrate for the other extension with 4-GlcNAc instead of 2-GlcNAc raises several domain (7). Defects in LARGE addition lead to dystroglycano- questions (see Fig. 1) (10). Was the 4-GlcNAc structure pathy and massive hypoglycosylation of -dystroglycan (71, observed a cell culture artifact from overexpression of a recom- 72). Of note, LARGE is down-regulated in certain metastatic binant -dystroglycan fragment in HEK293 cells? If not, which cancers, and its forced expression down-regulates motility of GlcNAc transferase is responsible for this activity (multiple cancer cells (73). The LARGE-dependent repeating disaccha- GlcNAc transferases can add a 4-GlcNAc structure onto man- ride appears to be the key for -dystroglycan binding to extra- nose residues in N-linked structures, including GnT-III, GnT- cellular matrix partners, but where this repeat is attached to IV, and GnT-VI), and does its loss induce dystroglycanopathy? O-mannosylated structures is unclear (73). Presumably, the Also, if the functionally glycosylated structure is extended via a repeat is somewhere on the other side of the phosphate that is 4-GlcNAc, what is the role of the POMGnT1 enzyme that, attached to the initiating mannose in a 6-linkage (Fig. 1). Over- when absent, clearly leads to dystroglycanopathy? expression of LARGE has been shown to partially rescue func- Fukutin and FKRP—The fukutin and FKRP proteins are tion in cells derived from patients with mutations in other gly- highly homologous to one another and currently of unknown cosyltransferases of the O-mannose pathway (2). This is function. A retrotransposon insertion in the 3-UTR of fukutin consistent with data obtained by Patnaik and Stanley (74), who is the most common cause of Fukuyama CMD, a dystrogly- demonstrated, using CHO mutant cell lines, that the LARGE- canopathy (62). In Japan, Fukuyama CMD is the second most dependent glycan modification could occur on O-GalNAc and common form of muscular dystrophy (Duchenne muscular N-glycan structures when O-mannosylation was abolished. dystrophy is the first) (63). Besides the insertion event in fuku- Alternatively, given that the mutations in POMGnT1 and tin, point mutations in fukutin and FKRP are also observed in POMT1 in patient cells that could be rescued by LARGE were various dystroglycanopathies (3, 64–66). Although it has been not null mutations, it is possible that overexpression of LARGE suggested that they are putative Golgi-localized glycosyltrans- could modify O-mannosyl glycans that were present at low lev- ferases, they do not fit into any established CAZy glycosyltrans- els. Exactly how the LARGE structure that appears to be key for ferase family, and mutation of the DXD domain in FKRP does function is attached to the O-mannose structure is a major out- not appear to alter functional glycosylation of -dystroglycan standing question in the field, along with where the LARGE- (67). Both proteins are part of the nucleotidyltransferase super- modified O-mannose-initiated glycans are attached to -dys- family and do contain LicD domains, which have been impli- troglycan (and potentially other proteins). cated in phosphorylcholine transfer to sugars in a 6-linkage, Glycosyltransferase-like Domain-containing 2 Protein forming a phosphodiester (68). Recent work by Beedle et al. (69) (GTDC2)—The most recent protein associated with CMD is has demonstrated that -dystroglycan isolated from fukutin GTDC2 (75). This glycosyltransferase belongs to the CAZy knock-out animals has exposed phosphates as opposed to phos- inverting GT61 family. Defects in this gene are seen in patients phodiesters, which are critical for functional glycosylation. presenting with Walker-Warburg syndrome, and knockdown Thus, although these putative enzymes are clearly involved in of this gene in zebrafish recapitulated the phenotype of the formation of the functional O-mannose-initiated glycans knockdown of POMT1 (75). It was speculated that this enzyme important for binding to extracellular proteins, their exact might be a xylosyltransferase (GT61 does contain 1,2-xylosyl- functions remain a mystery. transferases) (75). Sequence comparison showed that this UDP-Xyl:GlcUA 1,3-Xylosyltransferase and UDP-GlcUA: enzyme also has high homology to the recently described secre- Xyl 1,3-Glucuronosyltransferase (LARGE1 and LARGE2)— tory pathway-localized protein O--N-acetylglucosaminyl- LARGE1 and its close homolog, LARGE2, catalyze the same transferase (EGF domain-specific O-GlcNAc transferase) (76, reactions with slightly different biochemical properties, and 77). The actual activity of this enzyme and what role it plays both enzymes contain two different glycosyltransferase specifically in producing functional glycan-dependent protein domains (70). The N-terminal glycosyltransferase domain is a associations related to CMD remain to be elucidated. member of the CAZy retaining mechanism GT8 family and Conclusions catalyzes the transfer of Xyl in an 1,3-linkage to GlcUA (7). The C-terminal glycosyltransferase domain is a member of the Although substantial progress has been made in the last dec- CAZy inverting mechanism GT49 family and catalyzes the ade in uncovering enzymes and proteins that modulate the transfer of GlcUA in a 1,3-linkage to Xyl (7). In this way, the O-mannosylation pathway and that cause CMD, many ques- enzyme can build the repeating disaccharide -3-GlcUA-3- tions remain to be answered. As noted above, several of the 6932 JOURNAL OF BIOLOGICAL CHEMISTRY VOLUME 288 • NUMBER 10 •MARCH 8, 2013 MINIREVIEW: O-Mannosylation and CMD 662–675 putative enzymes are poorly characterized in terms of their pre- 9. Hara, Y., Kanagawa, M., Kunz, S., Yoshida-Moriguchi, T., Satz, J. S., Ko- ferred substrates and actual enzymatic activity. For the more bayashi, Y. M., Zhu, Z., Burden, S. J., Oldstone, M. B., and Campbell, K. P. defined glycosyltransferases, little work has been done to estab- (2011) Like-acetylglucosaminyltransferase (LARGE)-dependent modifi- lish genotype-phenotype correlations with the existing muta- cation of dystroglycan at Thr-317/319 is required for laminin binding and tions. Clearly, based on the fact that at least one-third of arenavirus infection. Proc. Natl. Acad. Sci. U.S.A. 108, 17426–17431 patients with dystroglycanopathy do not have defects in the 10. Yoshida-Moriguchi, T., Yu, L., Stalnaker, S. H., Davis, S., Kunz, S., Mad- son, M., Oldstone, M. B., Schachter, H., Wells, L., and Campbell, K. P. described gene products, there are other enzymes/proteins to (2010) O-Mannosyl phosphorylation of -dystroglycan is required for be discovered and characterized. Although substantial progress laminin binding. Science 327, 88–92 in determining the extracellular matrix-binding glycan struc- 11. Stalnaker, S. H., Hashmi, S., Lim, J. M., Aoki, K., Porterfield, M., Gutierrez- tures has been made in the last few years, a full description of Sanchez, G., Wheeler, J., Ervasti, J. M., Bergmann, C., Tiemeyer, M., and these structures remains to be presented. The protein sub- Wells, L. (2010) Site mapping and characterization of O-glycan structures strates for the O-mannosylation pathway have yet to be eluci- on -dystroglycan isolated from rabbit skeletal muscle. J. Biol. Chem. 285, 24882–24891 dated, with only a few putative proteins besides -dystroglycan 12. Nilsson, J., Nilsson, J., Larson, G., and Grahn, A. (2010) Characterization being identified to date. This may be particularly important of site-specific O-glycan structures within the mucin-like domain of given that the phenotypes observed in the dystroglycanopathies -dystroglycan from human skeletal muscle. Glycobiology 20, 1160–1169 clearly overlap but also exceed those observed in Duchenne 13. Stalnaker, S. H., Stuart, R., and Wells, L. (2011) Mammalian O-mannosy- muscular dystrophy (65, 78). Thus, like all good science, the lation: unsolved questions of structure/function. Curr. Opin. Struct. Biol. cohort of scientists/clinicians in this field have made substan- 21, 603–609 14. Barresi, R., and Campbell, K. P. (2006) Dystroglycan: from biosynthesis to tial advances while creating more questions that need to be pathogenesis of human disease. J. Cell Sci. 119, 199–207 pursued if we are to better understand the disease-relevant 15. Ervasti, J. M., Ohlendieck, K., Kahl, S. D., Gaver, M. G., and Campbell, K. P. pathway of protein O-mannosylation. (1990) Deficiency of a glycoprotein component of the dystrophin complex in dystrophic muscle. Nature 345, 315–319 16. Hoffman, E. P., Brown, R. H., Jr., and Kunkel, L. M. (1987) Dystrophin: the Acknowledgments—I thank all of the members of my laboratory as protein product of the Duchenne muscular dystrophy locus. 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(2008) Muscular dystrophies ton, M., Brown, S. C., Muntoni, F., Kröger, S., and Blake, D. J. (2002) due to glycosylation defects. Neurotherapeutics 5, 627–632 MARCH 8, 2013• VOLUME 288 • NUMBER 10 JOURNAL OF BIOLOGICAL CHEMISTRY 6935 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Biological Chemistry American Society for Biochemistry and Molecular Biology

The O-Mannosylation Pathway: Glycosyltransferases and Proteins Implicated in Congenital Muscular Dystrophy *

Journal of Biological Chemistry , Volume 288 (10) – Mar 8, 2013

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American Society for Biochemistry and Molecular Biology
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Copyright © 2013 Elsevier Inc.
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0021-9258
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10.1074/jbc.r112.438978
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Abstract

MINIREVIEW THE JOURNAL OF BIOLOGICAL CHEMISTRY VOL. 288, NO. 10, pp. 6930 –6935, March 8, 2013 © 2013 by The American Society for Biochemistry and Molecular Biology, Inc. Published in the U.S.A. the plasma membrane, most notably dystroglycan (18). Dystro- The O-Mannosylation Pathway: glycan is a single gene product (DAG1) that is processed into Glycosyltransferases and two subunits: -dystroglycan, that is a transmembrane protein that interacts with dystrophin in the cytoplasm, and -dystro- Proteins Implicated in glycan, which is a soluble secreted glycoprotein that interacts Congenital Muscular Dystrophy with both -dystroglycan and multiple components of the Published, JBC Papers in Press, January 17, 2013, DOI 10.1074/jbc.R112.438978 extracellular matrix, such as laminin, perlecan, pikachurin, Lance Wells neurexin, and agrin (18–23). These extracellular matrix pro- From the Complex Carbohydrate Research Center and Department of teins recognize and bind the unusual glycan structures on Biochemistry and Molecular Biology, University of Georgia, -dystroglycan. Thus, proper glycosylation of -dystroglycan is Athens, Georgia 30602 essential for binding to extracellular matrix components (24). Although -dystroglycan is both N- and O-linked glycosylated, Several forms of congenital muscular dystrophy, referred to as it is the O-linked glycans that are essential for proper function dystroglycanopathies, result from defects in the proteinO-man- (25). In terms of O-linked glycosylation, -dystroglycan con- nosylation biosynthetic pathway. In this minireview, I discuss 12 tains both classical mucin-like O-GalNAc-initiated glycans and proteins involved in the pathway and how they play a role in the the more unusual O-Man-initiated glycans (11). Multiple stud- building of glycan structures (most notably on the protein ies have clearly demonstrated that it is the O-mannosylated -dystroglycan) that allow for binding to multiple proteins of glycan structures that serve as binding sites for laminin and the extracellular matrix. presumably other extracellular matrix proteins (18–23). Inter- estingly, it appears to be these same essential structures that are recognized by the antibody IIH6 and that are used as cellular Although O-mannosylation of mammalian proteins was binding sites by some arenaviruses (9, 26). observed almost 35 years ago (1), it was not until the turn of the The initial O-mannose residue is added to serines and thre- millennium that the importance of this protein post-transla- onines of -dystroglycan and other proteins that have not been tional modification pathway began to be appreciated. In the clearly defined but certainly must exist in the endoplasmic early 2000s, multiple groups established that deficiencies of reticulum (ER) (27, 28). Multiple sites of O-mannosylation (and enzymes in this pathway result in multiple forms of congenital O-GalNAcylation) on -dystroglycan have been established (8, muscular dystrophy (CMD) that have now been termed dys- 11, 12). This O-mannose can then be extended to create a troglycanopathies (2–6). Recent work has begun to unravel the variety of glycan structures (Fig. 1) (reviewed recently in structures of the functional glycans that are altered and to iden- Refs. 13 and 29). In terms of how O-mannose-extended gly- tify sites of modification on -dystroglycan (7–12), the most can structures are important for binding to the extracellular well characterized and clearly functionally relevant O-manno- matrix, two recent studies have made substantial contributions sylated protein (13, 14). While briefly describing the dystro- (7, 10). It has been demonstrated on -dystroglycan that a phin-dystroglycan complex and the diversity of O-mannosy- GalNAc-3-GlcNAc-4-Man structure that is phosphorylated lated structures, this minireview will primarily highlight the at the 6-position of mannose and further extended by an enzymes and proteins that are known to be defective in unknown moiety on the distal side of the phosphate, forming a dystroglycanopathies. phosphodiester structure, is essential for binding to extracellu- Several forms of muscular dystrophy result at least in part lar matrix proteins (10). Most recently, it has been proposed from defects in the dystrophin-glycoprotein complex (15, 16). that a key component of this unknown extension from the This complex serves to link the actin cytoskeleton to the extra- phosphate contains the repeating disaccharide -3-GlcUA-3- cellular matrix via a complex of cytosolic proteins and plasma Xyl- (7). membrane-localized glycoproteins (17). Duchenne muscular Other recent reviews have focused on the structures, sub- dystrophy, which is the most common form of muscular dys- strates, and functional implications of the O-mannosylation trophy, is an X-linked recessive disorder resulting from loss of pathway and the phenotypes observed in the various muscular expression of functional dystrophin, a cytoplasmic actin-bind- dystrophies (13, 14, 17, 24, 29, 30). Here, I review the enzymes/ ing protein (16). Dystrophin is connected to a set of proteins at proteins of the pathway that have been implicated in CMD. * This work was supported, in whole or in part, by National Institutes of Health Enzymes/Proteins of the Pathway Grant P41RR018502 from NIGMS (to L. W., senior investigator). This work was also supported by the Georgia Research Alliance (to Lars G. Ljungdahl, Over the last decade, a variety of enzymes and proteins have investigator, and L. W.). This is the fourth article in the Thematic Minireview been implicated in the O-mannosylation pathway. Here, I focus Series on Glycobiology and Extracellular Matrices: Glycan Functions Per- primarily on the human proteins involved in the pathway that, vade Biology at All Levels. To whom correspondence should be addressed. E-mail: lwells@ccrc. when defective, have been shown to cause CMD, specifically uga.edu. dystroglycanopathies (Table 1). It should be noted that at least The abbreviations used are: CMD, congenital muscular dystrophy; ER, endo- one-third of dystroglycanopathies are of unknown genetic eti- plasmic reticulum; GlcUA, glucuronic acid; DPM, dolichol-phosphate man- nose; CDG, congenital disorders of glycosylation; GnT, GlcNAc-transferase. ology and do not have defects in the known gene products 6930 JOURNAL OF BIOLOGICAL CHEMISTRY VOLUME 288 • NUMBER 10 •MARCH 8, 2013 This is an Open Access article under the CC BY license. MINIREVIEW: O-Mannosylation and CMD Dolichyl-phosphate-mannose:Protein Mannosyltransferase (POMT1/2)—Initial O-mannosylation of proteins in the ER is catalyzed by POMT1/2 using DPM as the donor (39, 40). POMT1 and POMT2 belong to the inverting GT39 family in the CAZy Database. The proper expression of both proteins together is required for the catalysis of this first step in the O-mannosylation pathway (40, 41). Multiple mutations in both genes are causal for CMD, and complete loss-of-function muta- tions cause Walker-Warburg syndrome, the most severe of the dystroglycanopathies (42–49). Localization of these enzymes in the ER infers that O-mannosylation precedes classical mucin-like O-GalNAcylation of proteins in the secretory path- way. A recent study has demonstrated that O-mannosylation appears to modulate O-GalNAc addition and site selection (50). FIGURE 1. O-Mannose structures. O-Man-initiated glycans can be elabo- rated into linear or branched structures. A key structure for binding to extra- Furthermore, loss of O-mannosylation would potentially pro- cellular matrix proteins is not fully resolved but contains a phosphodiester vide novel sites for the polypeptide GalNAc transferases in the linkage, and a component of the X moiety is likely to be the LARGE-catalyzed cis-Golgi. Thus, loss of O-mannosylation may alter O-GalNAc repeating disaccharide. Green circles, Man; blue squares, GlcNAc; yellow square, GalNAc; yellow circles, Gal; pink diamonds, Neu5Ac; red triangles, Fuc; addition on proteins, and this “gain of modification” could be orange star, Xyl; blue/white diamond, GlcUA. GlcNAc residues on the O-Man responsible for some of the observed phenotypes in CMD. added in the 2-position are drawn up to the left, in the 4-position straight up, and in the 6-position up to the right. Asymmetric branched structures are 2-C-Methyl-D-Erythritol 4-Phosphate Cytidylyltransferase- drawn in only one possible configuration, although isomeric structures are like Protein (Isoprenoid Synthase Domain-containing (ISPD))— likely to exist. ISPD is not predicted to be a glycosyltransferase, yet mutations involved to date in the O-mannosylation pathway. Further- in this protein cause Walker-Warburg syndrome with clear loss more, several of the enzymes needed to build the array of struc- of -dystroglycan functional glycosylation (51, 52). This tures observed (Fig. 1) are common to multiple pathways, such enzyme has high similarity to an enzyme in the non-mevalonate as the sialyltransferases, fucosyltransferases, and galactosyl- pathway for isoprenoid synthesis (53). However, mammals are transferases, and are not discussed here, as there is no evidence thought to use only the mevalonate pathway, and several other to date for them being defective in CMD. Finally, O-mannosy- enzymes in the bacterial non-mevalonate pathway are not obvi- lation is an evolutionarily conserved post-translational modifi- ously conserved in higher animals (53). Thus, the role for this cation from yeast to man, and several model systems have pro- putative enzyme remains unclear, although it clearly impacts vided invaluable insights into the pathway (31–33). the ability of POMT1/2 to transfer O-mannose (52). Does the Dolichol-phosphate Mannose Synthase—Dolichol-phos- defect in ISPD affect other types of glycosylation that depend on phate mannose (DPM) is the donor for luminal ER mannosyla- dolichol-linked sugars? Does ISPD play a role in modification of tion, including N-, O-, and C-glycosylation as well as glycophos- dolichol-linked mannose? These questions have yet to be fully phatidylinositol anchor biosynthesis (34). DPM is synthesized explored. from GDP-Man and dolichol phosphate via an inverting mech- UDP-GlcNAc:O-Linked Mannose 1,2-N-Acetylglucosami- anism on the cytosolic side of the ER (34). This reaction is cat- nyltransferase (POMGnT1)—POMGnT1 catalyzes the exten- alyzed by the DPM synthase complex (34). The catalytic activity sion of the O-mannose-initiated structure with a GlcNAc in a is performed by DPM1, a dolichol-phosphate -D-mannosyl- 2-linkage and is a member of the CAZy GT13 family of invert- transferase belonging to the glycosyltransferase 2 (GT2) family ing enzymes (6). Mutations in this gene are observed in patients of the CAZy (Carbohydrate-Active enZYmes) Database (34). with multiple forms of dystroglycanopathy (6, 54–59). Mice DPM2 and DPM3 are ER-localized transmembrane proteins with a knock-out of this enzyme present with phenotypes con- that interact with the catalytic DPM1 protein to form a fully sistent with human muscle-eye-brain disease, a severe form of active DPM synthase complex (35). Causal mutations for a dys- CMD (55). Genotype-phenotype correlations have begun to be troglycanopathy phenotype along with type I congenital disor- established for this enzyme (54). This enzyme is localized in the ders of glycosylation (CDG) have been observed in DPM2 and cis-Golgi, and its action appears to be essential for not only DPM3 (36, 37). Although patient mutations in DPM1 cause a 2-extension but also 6-branching of the O-mannose moiety severe form of CDG (38), surprisingly, no dystroglycanopathy with GlcNAc (28). 6-Branching of the O-mannose is catalyzed or muscular dystrophy has been noted. Given the vital role of by UDP-GlcNAc:mannose 1,6-N-acetylglucosaminyltrans- DPM in multiple forms of glycosylation, it is perhaps not sur- ferase, GnT-Vb (GnT-IX) (60). Although GnT-Vb and O-man- prising that mutations in DPM2 and DPM3 cause severe pleio- nose branching is localized primarily to the brain, making the tropic phenotypes. Whether DPM2/3 mutations are truly gene an attractive potential affected target for undiagnosed causal for CMD remains controversial in the field. The proteins CMD with neurological complications, mice lacking GnT-Vb responsible for flipping the DPM to the lumen of the ER have alone or in combination with a knock-out of GnT-Va (which not been determined, and impairment of function of these pro- can partially compensate for O-Man branching in the absence teins would also likely lead to a plethora of complications of GnT-Vb) do not display any gross brain abnormalities or resembling both CMD and CDG, as observed for DPM2 and muscular dystrophy (61). Given the recent finding that the DPM3. 6-phosphomannose structure that was presumably extended MARCH 8, 2013• VOLUME 288 • NUMBER 10 JOURNAL OF BIOLOGICAL CHEMISTRY 6931 MINIREVIEW: O-Mannosylation and CMD TABLE 1 Enzymes/proteins involved in the O-mannosylation pathway and potentially CMD Gene Protein functions CAZy family DPM2 and DPM3 Facilitate DPM1-catalyzed formation of DPM GT2 (DPM1) POMT1 and POMT2 Protein O-Man transferase GT39 ISPD Unknown (putative enzyme) None POMGnT1 O-Man 2-GlcNAc transferase GT13 Fukutin and FKRP Unknown (LicD motif putative enzymes) None LARGE1 and LARGE2 Dual-activity glycosyltransferase: GlcUA 3-Xyl GT8/GT49 transferase and Xyl 3-GlcUA transferase GTDC2 Unknown (putative glycosyltransferase) GT61 with the functional glycan that is LARGE-dependent had an Xyl-, as each product of one domain is a substrate for the other extension with 4-GlcNAc instead of 2-GlcNAc raises several domain (7). Defects in LARGE addition lead to dystroglycano- questions (see Fig. 1) (10). Was the 4-GlcNAc structure pathy and massive hypoglycosylation of -dystroglycan (71, observed a cell culture artifact from overexpression of a recom- 72). Of note, LARGE is down-regulated in certain metastatic binant -dystroglycan fragment in HEK293 cells? If not, which cancers, and its forced expression down-regulates motility of GlcNAc transferase is responsible for this activity (multiple cancer cells (73). The LARGE-dependent repeating disaccha- GlcNAc transferases can add a 4-GlcNAc structure onto man- ride appears to be the key for -dystroglycan binding to extra- nose residues in N-linked structures, including GnT-III, GnT- cellular matrix partners, but where this repeat is attached to IV, and GnT-VI), and does its loss induce dystroglycanopathy? O-mannosylated structures is unclear (73). Presumably, the Also, if the functionally glycosylated structure is extended via a repeat is somewhere on the other side of the phosphate that is 4-GlcNAc, what is the role of the POMGnT1 enzyme that, attached to the initiating mannose in a 6-linkage (Fig. 1). Over- when absent, clearly leads to dystroglycanopathy? expression of LARGE has been shown to partially rescue func- Fukutin and FKRP—The fukutin and FKRP proteins are tion in cells derived from patients with mutations in other gly- highly homologous to one another and currently of unknown cosyltransferases of the O-mannose pathway (2). This is function. A retrotransposon insertion in the 3-UTR of fukutin consistent with data obtained by Patnaik and Stanley (74), who is the most common cause of Fukuyama CMD, a dystrogly- demonstrated, using CHO mutant cell lines, that the LARGE- canopathy (62). In Japan, Fukuyama CMD is the second most dependent glycan modification could occur on O-GalNAc and common form of muscular dystrophy (Duchenne muscular N-glycan structures when O-mannosylation was abolished. dystrophy is the first) (63). Besides the insertion event in fuku- Alternatively, given that the mutations in POMGnT1 and tin, point mutations in fukutin and FKRP are also observed in POMT1 in patient cells that could be rescued by LARGE were various dystroglycanopathies (3, 64–66). Although it has been not null mutations, it is possible that overexpression of LARGE suggested that they are putative Golgi-localized glycosyltrans- could modify O-mannosyl glycans that were present at low lev- ferases, they do not fit into any established CAZy glycosyltrans- els. Exactly how the LARGE structure that appears to be key for ferase family, and mutation of the DXD domain in FKRP does function is attached to the O-mannose structure is a major out- not appear to alter functional glycosylation of -dystroglycan standing question in the field, along with where the LARGE- (67). Both proteins are part of the nucleotidyltransferase super- modified O-mannose-initiated glycans are attached to -dys- family and do contain LicD domains, which have been impli- troglycan (and potentially other proteins). cated in phosphorylcholine transfer to sugars in a 6-linkage, Glycosyltransferase-like Domain-containing 2 Protein forming a phosphodiester (68). Recent work by Beedle et al. (69) (GTDC2)—The most recent protein associated with CMD is has demonstrated that -dystroglycan isolated from fukutin GTDC2 (75). This glycosyltransferase belongs to the CAZy knock-out animals has exposed phosphates as opposed to phos- inverting GT61 family. Defects in this gene are seen in patients phodiesters, which are critical for functional glycosylation. presenting with Walker-Warburg syndrome, and knockdown Thus, although these putative enzymes are clearly involved in of this gene in zebrafish recapitulated the phenotype of the formation of the functional O-mannose-initiated glycans knockdown of POMT1 (75). It was speculated that this enzyme important for binding to extracellular proteins, their exact might be a xylosyltransferase (GT61 does contain 1,2-xylosyl- functions remain a mystery. transferases) (75). Sequence comparison showed that this UDP-Xyl:GlcUA 1,3-Xylosyltransferase and UDP-GlcUA: enzyme also has high homology to the recently described secre- Xyl 1,3-Glucuronosyltransferase (LARGE1 and LARGE2)— tory pathway-localized protein O--N-acetylglucosaminyl- LARGE1 and its close homolog, LARGE2, catalyze the same transferase (EGF domain-specific O-GlcNAc transferase) (76, reactions with slightly different biochemical properties, and 77). The actual activity of this enzyme and what role it plays both enzymes contain two different glycosyltransferase specifically in producing functional glycan-dependent protein domains (70). The N-terminal glycosyltransferase domain is a associations related to CMD remain to be elucidated. member of the CAZy retaining mechanism GT8 family and Conclusions catalyzes the transfer of Xyl in an 1,3-linkage to GlcUA (7). The C-terminal glycosyltransferase domain is a member of the Although substantial progress has been made in the last dec- CAZy inverting mechanism GT49 family and catalyzes the ade in uncovering enzymes and proteins that modulate the transfer of GlcUA in a 1,3-linkage to Xyl (7). In this way, the O-mannosylation pathway and that cause CMD, many ques- enzyme can build the repeating disaccharide -3-GlcUA-3- tions remain to be answered. As noted above, several of the 6932 JOURNAL OF BIOLOGICAL CHEMISTRY VOLUME 288 • NUMBER 10 •MARCH 8, 2013 MINIREVIEW: O-Mannosylation and CMD 662–675 putative enzymes are poorly characterized in terms of their pre- 9. Hara, Y., Kanagawa, M., Kunz, S., Yoshida-Moriguchi, T., Satz, J. S., Ko- ferred substrates and actual enzymatic activity. For the more bayashi, Y. M., Zhu, Z., Burden, S. J., Oldstone, M. B., and Campbell, K. P. defined glycosyltransferases, little work has been done to estab- (2011) Like-acetylglucosaminyltransferase (LARGE)-dependent modifi- lish genotype-phenotype correlations with the existing muta- cation of dystroglycan at Thr-317/319 is required for laminin binding and tions. Clearly, based on the fact that at least one-third of arenavirus infection. Proc. Natl. Acad. Sci. U.S.A. 108, 17426–17431 patients with dystroglycanopathy do not have defects in the 10. Yoshida-Moriguchi, T., Yu, L., Stalnaker, S. H., Davis, S., Kunz, S., Mad- son, M., Oldstone, M. B., Schachter, H., Wells, L., and Campbell, K. P. described gene products, there are other enzymes/proteins to (2010) O-Mannosyl phosphorylation of -dystroglycan is required for be discovered and characterized. Although substantial progress laminin binding. Science 327, 88–92 in determining the extracellular matrix-binding glycan struc- 11. Stalnaker, S. H., Hashmi, S., Lim, J. M., Aoki, K., Porterfield, M., Gutierrez- tures has been made in the last few years, a full description of Sanchez, G., Wheeler, J., Ervasti, J. M., Bergmann, C., Tiemeyer, M., and these structures remains to be presented. The protein sub- Wells, L. (2010) Site mapping and characterization of O-glycan structures strates for the O-mannosylation pathway have yet to be eluci- on -dystroglycan isolated from rabbit skeletal muscle. J. Biol. Chem. 285, 24882–24891 dated, with only a few putative proteins besides -dystroglycan 12. Nilsson, J., Nilsson, J., Larson, G., and Grahn, A. (2010) Characterization being identified to date. This may be particularly important of site-specific O-glycan structures within the mucin-like domain of given that the phenotypes observed in the dystroglycanopathies -dystroglycan from human skeletal muscle. Glycobiology 20, 1160–1169 clearly overlap but also exceed those observed in Duchenne 13. Stalnaker, S. H., Stuart, R., and Wells, L. (2011) Mammalian O-mannosy- muscular dystrophy (65, 78). Thus, like all good science, the lation: unsolved questions of structure/function. Curr. Opin. Struct. Biol. cohort of scientists/clinicians in this field have made substan- 21, 603–609 14. Barresi, R., and Campbell, K. P. (2006) Dystroglycan: from biosynthesis to tial advances while creating more questions that need to be pathogenesis of human disease. J. Cell Sci. 119, 199–207 pursued if we are to better understand the disease-relevant 15. Ervasti, J. M., Ohlendieck, K., Kahl, S. D., Gaver, M. G., and Campbell, K. P. pathway of protein O-mannosylation. (1990) Deficiency of a glycoprotein component of the dystrophin complex in dystrophic muscle. Nature 345, 315–319 16. Hoffman, E. P., Brown, R. H., Jr., and Kunkel, L. M. (1987) Dystrophin: the Acknowledgments—I thank all of the members of my laboratory as protein product of the Duchenne muscular dystrophy locus. 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(2008) Muscular dystrophies ton, M., Brown, S. C., Muntoni, F., Kröger, S., and Blake, D. J. (2002) due to glycosylation defects. Neurotherapeutics 5, 627–632 MARCH 8, 2013• VOLUME 288 • NUMBER 10 JOURNAL OF BIOLOGICAL CHEMISTRY 6935

Journal

Journal of Biological ChemistryAmerican Society for Biochemistry and Molecular Biology

Published: Mar 8, 2013

Keywords: Carbohydrate Glycoprotein; Glycoprotein; Glycosylation; Muscular Dystrophy; Post-translational Modification; Congenital Muscular Dystrophy; Dystroglycan; O-Mannosylation

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