Glycobiology, 2000, Vol. 10, No. 7 645-648
© 2000 Oxford University Press
Transport of free and N-linked oligomannoside species across the rough endoplasmic reticulum membranes
Laboratoire de Chimie Biologique, CNRS-UMR 8576, Université des Sciences et Technologies de Lille, 59655 Villeneuve d’Ascq Cedex, France
Accepted on February 25, 2000;
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Abstract |
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 Top Abstract IntroductionEfflux of free oligomannosidesEfflux of glycopeptidesRetrotranslocation of...ConclusionReferences |
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The N-glycosylation process occurs in the rough endoplasmic reticulum. It requires the transport of glycosyl donors into the lumen and the exit of the glycosylated products toward the secretory pathway. Besides this main flow, the formation of free oligomannosides, glycopeptides, and misfolded glycoproteins which do not enter the secretory pathway and are cleared out of the endoplasmic reticulum by specific transports has been demonstrated. This review focuses on the export mechanisms of these three side products of the N-glycosylation process and discusses their physiological significance.
Key words: N-glycosylation/oligomannoside/endoplasmic reticulum/transport
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Introduction |
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TopAbstractIntroductionEfflux of free oligomannosidesEfflux of glycopeptidesRetrotranslocation of...ConclusionReferences |
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In eukaryotic cells, the rough endoplasmic reticulum (ER) plays a key role in the biosynthesis and the quality control of secretory and membrane glycoproteins. This requires an input of glycosyl donors into the system and an output of glycosylated products. With respect to the dolichol cycle, this input involves the transmembrane transport of mannose-phospho-dolichol (Man-P-Dol) and glucose-phospho-dolichol (Glc-P-Dol) as well as the Man5GlcNAc2-PP-Dol intermediate. The final Glc3Man9GlcNAc2-pyrophospho-dolichol is used as donor in an "en bloc" transfer reaction to asparagine residues of the acceptor protein. In the ER, the input also concerns the entry of UDP-Glc (Vanstapel and Blanckaert, 1988
; Castro et al., 1999) as a substrate for unfolded protein reglucosylation, a prerequisite for retention by calnexin or calreticulin. Once core glycosylation and folding are completed successfully, membrane and secretory glycoproteins are packaged into ER-to-Golgi transport vesicles. This constitutes the major pathway for the sorting of glycosylated proteins synthesized in the ER. Besides this main flow toward the Golgi apparatus, several different lines of research have demonstrated that free oligomannosides, glycopeptides, and misfolded glycoproteins do not follow the secretory pathway but are transported across the membrane from the ER lumen to the cytosol.
This review will focus on what is known about the export mechanisms of these three different molecular species. We will also discuss the physiological significance of this efflux of glycosylated molecules produced during the N-glycosylation process.
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Efflux of free oligomannosides |
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TopAbstractIntroductionEfflux of free oligomannosidesEfflux of glycopeptidesRetrotranslocation of...ConclusionReferences |
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It has been demonstrated in several biological models that the synthesis of glycoconjugates generates substantial quantities of free oligomannosides in the lumen of the rough endoplasmic reticulum (for review see Cacan and Verbert, 1999
; Moore, 1999). This material is in part constituted of oligomannosides possessing di-N-acetyl-chitobiosyl moieties at the reducing end (mainly OS-Gn2), derived from the precursor Glc3Man9GlcNAc2 structure. These originate from the hydrolysis of oligosaccharide-PP-dolichol, presumably as a result of transfer to water. Several lines of evidence, such as the effect of EDTA (Anumula and Spiro, 1983) or cycloheximide (Villers et al., 1994), indicate that this phenomenon was enhanced when the level of newly synthesized proteins to be glycosylated was low. This material does not follow the secretory pathway since it is not recovered in the cell culture medium. However, pulse chase experiments have shown that this oligosaccharide material is recovered in the cytosol as oligomannosides possessing a single GlcNAc residue (OS-Gn1) at the reducing end. Moore and Spiro (1994) have clearly shown that oligomannosides are transported into the cytosol as OS-Gn2. We demonstrated (Cacan et al., 1996) that it is further cleaved by a cytosolic chitobiase. This cleavage is a prerequisite to the action of cytosolic mannosidase, which is known to act specifically on OS-Gn1 species (Grard et al., 1996). Sequential action of cytosolic chitobiase and 
-mannosidase leads to the formation of a specific Man5Gn1 isomer: Man1,2 Man1,2 Man1,3 (Man1,6) Manß1,4 GlcNAc, (Kmiécik et al., 1995; Saint-Pol et al., 1997). This compound is finally targeted to the lysosomes where it is further degraded into monosaccharides. The key step of this oligomannoside trafficking is the transport from the ER lumen to the cytosol by a specific carrier which has been thoroughly studied (Moore et al., 1995; Moore, 1998). In vitro experiments have shown that the carrier is effective only if ATP is available for hydrolysis. It was demonstrated that the transport is inhibited if the transport assay medium is depleted of calcium ions; if thapsigargin, an inhibitor of [Ca++-Mg ++]ATPase, is added; or if calcium ionophore is present. These observations suggest that the transport process requires the presence of calcium sequestered in the lumen of ER.
Regarding its specificity, this carrier recognizes the terminal nonreducing mannosyl part of the free oligomannosides. Indeed, competitive inhibition of transport is observed during in vitro assays in the presence of mannose derivatives modified at the carbon 1 position (Moore, 1998). Moreover, it has been shown by inhibiting glucosidases with castanospermine in vivo, that oligomannosides which have retained the glucose residues are not transported (Moore et al., 1995). It is interesting to note that the transport process is suspected to be unidirectional since the presence of 1mM OS-Gn2 outside the vesicles did not inhibit the exit transport (Moore, 1998). Assuming that the lumenal concentration of OS-Gn2 does not exceed 1 mM, it can be postulated that this transport process can operate against a concentration gradient.
As proposed (Verbert and Cacan, 1999), this efflux of oligomannosides provides an ER lumen clearing mechanism. It is indeed suspected that free oligomannosides would otherwise compete for oligomannoside recognizing proteins such as glycosidases, chaperones, and glycosyltransferases. In addition, free oligomannosides would follow the secretory pathway and interfere with the Golgi processing machinery.
Another possible function for this oligomannoside trafficking would be to provide the cytosol with potential oligomannoside ligands for lectins which have been described in other subcellular locations such as the nucleus. However this possibility still needs to be explored experimentally.
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Efflux of glycopeptides |
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TopAbstractIntroductionEfflux of free oligomannosidesEfflux of glycopeptidesRetrotranslocation of...ConclusionReferences |
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Another source of OS-Gn2 in the cytosol could be the cleavage by a cytosolic peptide N-glycanase (PNGase) of glycopeptides which are exported from the ER lumen as described by Römish and Ali (1997). The first observation was made by Geetha-Habib et al. (1990)
, who investigated the fate of peptides injected in the cytosol of Xenopus oocytes. They observed that the peptides are glycosylated but are neither recovered in the Golgi nor secreted. In fact, they are degraded and their degradation is inhibited by chloroquine thereby indicating it is achieved by lysosomal enzymes. This result implies that glycopeptides have first to enter the ER to be glycosylated and then are re-exported to the cytosol to be finally degraded in lysosomes. This export of glycopeptides has been further studied in Saccharomyces cerevisiae and compared to the Golgi-directed vesicular transport of glycoproteins (Römish and Schekman, 1992). Both processes are cytosol-, temperature-, and ATP-dependent, but the traffic of glycopeptides is not inhibited by antibodies against two proteins essential for the budding of transport vesicles (Sec23p and p105). Thus, the released glycopeptides, in contrast to glycoproteins, are not entrapped into vesicles since they do not acquire yeast Golgi specific -1,6 linked mannose residues.
This same transmembrane export mechanism has been described in mammalian cells (dog pancreas, rat liver), but in this case the glycopeptides are not recovered in the cytosol due to their rapid degradation by a cytosolic PNGase (Römish and Ali, 1997). Experiments performed with ER and cytosol from heterologous sources have indicated that the process is conserved throughout evolution and thus appears to be of importance.
This transport mechanism has been studied by Ali and Field (2000). It was shown to be distinct from the oligomannoside carrier previously described by Moore (1998), through a number of criteria. First, glycopeptide export requires Mg++ but not Ca++; second, thapsigargicin and calcium ionophore stimulates the export; and third, the presence of glucosyl residues does not impair the export. Furthermore it has been recently shown in yeast that export of glycopeptides is not affected by the structure of their oligosaccharide chains (Suzuki and Lennarz, 2000).
Neither the physiological significance of this phenomenon nor the origin of the glycopeptides formed in the lumen of the ER are yet understood. They could originate from glycosylation of peptides which have entered the ER lumen. Indeed such peptide carriers have been described (Kleijmeer et al., 1992). On the other hand, they could be generated through proteolytic cleavage of glycoproteins in the ER. The latter process could be a pathway parallel to the proteasome dependent degradation of newly synthesized glycoproteins.
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Retrotranslocation of glycoproteins |
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TopAbstractIntroductionEfflux of free oligomannosidesEfflux of glycopeptidesRetrotranslocation of...ConclusionReferences |
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Wiertz (1996a)
first demonstrated that infection with human cytomegalovirus induces the degradation of the N-glycosylated major histocompatibility complex (MHC) class I molecules of host cells. They showed that this degradation process requires the retrotranslocation of the glycoprotein from the ER lumen to the cytosol to be further degraded by the proteasome. They have shown the presence in the cytosol of a deglycosylated MHC intermediate suggesting the action of a putative peptide N-glycanase, indicating that the protein has to be retrotranslocated in its glycosylated form. A similar retrotranslocation of the glycosylated form of glycoproteins has also been demonstrated for misfolded MHC class I heavy chain in nonvirally infected cells (Hughes et al., 1997) for T-cell receptor -chain (Yu et al., 1997) and for truncated ribophorin I (de Virgilio et al., 1998).
The retrotranslocation involves the Sec 61 complex in what appears to be a reversal of the reaction by which nascent peptide chains are translocated into the endoplasmic reticulum (Bonifacino, 1996; Wiertz, 1996b; Pilon, 1997; Plemper et al., 1997). This reverse transport through the translocon machinery strongly suggests that the glycoproteins have to be unfolded to reengage the Sec 61 complex for translocation thus leading to cytosolic destruction.
So far, the putative driving forces would be the association either with calnexin (McCracken and Brodsky, 1996; Qu et al., 1996; Liu et al., 1999), Kar2p/Bip (Plemper et al., 1997; Skowronek et al., 1998; Brodsky et al., 1999), or PDI (Gillece et al., 1999) in the lumenal side, and the association with heat-shock protein (hsp 70) in the cytosolic compartment (Fischer et al., 1997). The ATPase activity associated to proteasome could also be involved as suggested by Mayer et al. (1998).
However, cytosolic deglycosylation of retrotranslocated glycoprotein has to occur before ubiquitination and degradation. This observation raises the question of the occurrence of cytosolic endoglycanases. Two endoglycanase activities have been already pointed out in the cytosol: a ß-endo N-acetylglucosaminidase described by Pierce et al., 1979, 1980), and more recently a PNGase characterized and isolated by Suzuki et al., 1994, 1998). By metabolic labeling of the glycan moieties we have correlated the presence of OS-Gn1 in the cytosol with the degradation of newly synthesized glycoproteins (Villers et al., 1994; Duvet et al., 1998). Thus, two deglycosylation pathways are possible: the complete deglycosylation by PNGase releasing OS-Gn2 which is immediately degraded to OS-Gn1 by a cytosolic chitobiase (Cacan et al., 1996) or the cleavage of the glycoprotein by the ß-endo N-acetylglucosaminidase releasing directly OS-Gn1. The latter process produces glycoproteins with a single GlcNAc attached to their N-glycosylation sites. Such intermediates have been recently reported in recombinant human interferon-
produced in CHO and insect cells (Hooker et al., 1999).
This whole process appears to be correlated with the expression of misfolded or misassembled glycoproteins. This suggests that this glycoprotein efflux is used to clear the ER from such denatured glycoproteins as a result of quality control.
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Conclusion |
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TopAbstractIntroductionEfflux of free oligomannosidesEfflux of glycopeptidesRetrotranslocation of...ConclusionReferences |
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The N-glycosylation process can produce four different types of glycosylated species: correctly folded glycoproteins, misfolded or misassembled glycoproteins, glycopeptides, and free oligomannosides. Among these four end products, only the correctly folded glycoproteins are transported to the Golgi apparatus for plasma membrane insertion or for secretion. Thus, the three other ones have to be eliminated from the ER lumen. Presumably, if they would follow the secretion pathway they would interfere and compete with the glycosylation machinery within the Golgi. This review has discussed three different export processes for each of these N-glycosylation side products. Indeed, this appears to answer why a more strict control of the N-glycosylation early steps (i.e., the dolichol cycle) does not seem to be exerted. So far, few reports have described the regulation of the dolichol cycle and these mainly concern the inhibition of the formation of GlcNAc-PP-Dol by Man-P-Dol (Kean, 1982
) and the control of Man-P-Dol synthase activity by phosphorylation (Banerjee et al., 1987). This could suggest that regulation might occur at other downstream steps such as the degradation of unsuitable products formed in excess. This would explain the degradation of oligosaccharide-PP-Dol into soluble OS-Gn2 and the degradation of misfolded glycoproteins. On the other hand, glycopeptides can originate from proteolytic cleavage of glycoproteins. However, this raises the question of a subcompartment of ER allowing the segregation of the biosynthetic and degradation pathways. It can be equally postulated that they originate from glycosylation of cytosolic peptides which have entered the ER. The possibility of such a posttranslational glycosylation reaction has already been demonstrated by numerous experiments involving oligosaccharyl transferase assays performed with synthetic peptides. It is interesting to note that whatever is the origin of the glycosylated species transported to the cytosol (free oligomannosides, glycopeptides, retrotranslocated glycoproteins), the end product is a unique oligosaccharide Man5GlcNAc1 specifically recognized by a lysosomal carrier for entry and degradation. The different transports of free and N-linked oligomannoside species across the rough endoplasmic reticulum membranes are summarized in the Figure 1.
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Footnotes |
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1 To whom correspondence should be addressed
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