MINIREVIEW
Oligosaccharide-based Information in Endoplasmic Reticulum Quality Control and Other Biological Systems*

Mark A. LehrmanDagger

From the Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9041

    Oligosaccharides as Information Carriers
TOP
Oligosaccharides as Information...
Oligosaccharide-based...
Endoplasmic Reticulum...
Defective Synthesis or...
N-Linked Glycosylation as an...
Insights from Other Biological...
Summary and Perspectives
REFERENCES

Glycosidically linked sugar polymers are well known as nutritional and structural molecules, and it is now clear that they also have essential roles as carriers of biological information. The constituent sugar residues contain multiple hydroxyl groups capable of forming complex arrangements of hydrogen bonds. Sugars are often modified with amino, N-acetyl, carboxyl, phosphate, and sulfate groups, permitting more varied interactions than those achieved with hydroxyls. Many different sugars occur in nature, and these can be coupled in numerous ways through alpha  or beta  glycosidic linkages of their hydroxyls to form oligosaccharides (with relatively few sugars) and polysaccharides (with many sugars) (1). For example, there are eight different ways to couple the anomeric carbon (no. 1) of one residue of glucose to the nonanomeric carbons (no. 2, 3, 4, or 6) of another. Sugar polymers are also distinguished from other biological polymers by facile formation of both linear and branched structures. For example, the beta 1,4-linked mannose residue in asparagine (N)-linked oligosaccharides is always linked to at least three other sugars as indicated in Fig. 1. Oligosaccharides that carry information are usually coupled to chemically distinct units termed aglycones that themselves are not carbohydrates, but typically are proteins or lipids, and whose biological properties can be dramatically changed by the oligosaccharide.


View larger version (29K):
[in this window]
[in a new window]
 
Fig. 1.   Information encoded by N-linked processing intermediates in the ER. The structure of Glc3Man9GlcNAc2 linked to asparagine and the residues removed by sequential glycosidase reactions are shown. The information contents of Glc3Man9GlcNAc2 (a) and the products of each processing reaction (b-e) are indicated. The A-isomer of Man8GlcNAc2 is formed by Golgi endomannosidase cleavage of the linkage marked with an asterisk. The B-isomer of Man8GlcNAc2 results from reaction (e).

The purpose of this minireview is to explore the roles of oligosaccharides as carriers of intra- and intercellular information with emphasis on the relationships between oligosaccharide metabolism, quality control, and stress responses of the endoplasmic reticulum (ER).1

    Oligosaccharide-based Information in ER Protein Quality Control
TOP
Oligosaccharides as Information...
Oligosaccharide-based...
Endoplasmic Reticulum...
Defective Synthesis or...
N-Linked Glycosylation as an...
Insights from Other Biological...
Summary and Perspectives
REFERENCES

The process of quality control for nascent proteins in the lumen of the ER is an excellent example of oligosaccharide-based information. Specifically, information-carrying N-linked oligosaccharides on newly synthesized ER glycoproteins are continuously altered during folding and assembly to reflect the status of the glycoproteins and to promote interaction(s) with appropriate components of the quality control machinery (2). Fig. 1 summarizes the five common N-linked intermediates that occur in the ER, the information they carry, and the enzymes that govern their formation. Additional details can be found in recent excellent reviews by Parodi (3) and Spiro (4).

Glc3Man9GlcNAc2-- This oligosaccharide is transferred cotranslationally by the multisubunit enzyme oligosaccharyltransferase from the lipid-linked oligosaccharide (LLO) Glc3Man9GlcNAc2-P-P-dolichol to sterically accessible asparaginyl residues in the context Asn-Xaa-Ser/Thr on nascent proteins in the ER lumen (5). Attachment of this oligosaccharide therefore signifies translocation of the polypeptide into the ER lumen but not necessarily completion of translation. Although the triglucosyl sequence of Glc3Man9GlcNAc2 is important for recognition by oligosaccharyltransferase (4), no specific function or informational content has been reported for Glc3Man9GlcNAc2 on glycoproteins, although its hydrophilic character promotes protein folding (see below).

Glc2Man9GlcNAc2-- With a half-time of less than 2 min (6) Glc3Man9GlcNAc2-protein is processed to Glc2Man9GlcNAc2 by a castanospermine (CSN)-sensitive enzyme, glucosidase I. No specific informational role has been reported for Glc2Man9GlcNAc2. Both Glc2Man9GlcNAc2 and Glc1Man9GlcNAc2 are substrates for glucosidase II, which is also inhibited by CSN.

Glc1Man9GlcNAc2-- The presence of this oligosaccharide indicates that the protein to which it is attached is ready to interact with a lectin-chaperone,2 calnexin (CNX) or calreticulin (CRT), to achieve the proper tertiary or quaternary structure. Glc1Man9GlcNAc2-protein can be formed by digestion of Glc2Man9GlcNAc2-protein by glucosidase II, with a half-time of ~5 min in vivo (6) or by reglucosylation of Man9GlcNAc2-protein (see below). Many glycoproteins require Glc1Man9GlcNAc2-dependent interactions with CNX or CRT for efficient folding, assembly, and export from the ER (3, 4, 7). CNX (8) and CRT (9) are clearly lectins, and Glc1Man9GlcNAc2 can bind directly whether it is free or linked to protein. Association constants for CNX are in the range of 4-5 × 105 M-1 (10). Glc1Man(5-9)GlcNAc2, but not Glc1Man4GlcNAc2, bind to CNX (11) and CRT (9), and the three mannosyl residues that form the "arm" to which glucose is attached also contribute to binding (11). Because only oligosaccharides with a single alpha -1,3-linked glucosyl residue bind, oligosaccharide ligands for these lectin-chaperones are referred to collectively as monoglucosylated oligosaccharides.

In addition to their lectin activities, both CNX (12) and CRT (13) have efficient oligosaccharide-independent chaperone activities in vitro. There is abundant evidence that many glycoprotein folding intermediates first interact with CNX and CRT in a lectin-dependent manner, followed by formation of oligosaccharide-independent complexes (3, 8). It is probable that the chaperone activities of CNX and CRT contribute to glycoprotein folding in such complexes. Oligosaccharide-independent interactions with CNX and CRT would likely involve hydrophobic surfaces on glycoprotein folding intermediates. However, such hydrophobic interactions cannot be easily distinguished experimentally from irrelevant hydrophobic interactions that would also be anticipated with partially unfolded glycoproteins. Hence, the two-state mechanism has been difficult to prove (3). The situation has been complicated further by reports of some "lectin-only" and "lectin-independent" complexes of glycoprotein folding intermediates with CNX (3). It is possible that the mechanism used depends upon the specific glycoprotein in question. Resolution of this controversy may require the determination of three-dimensional structures of lectin-chaperone·glycoprotein complexes.

Glc1Man9GlcNAc2 is an excellent substrate for the Golgi endomannosidase, which releases a Glcalpha 1,3Man disaccharide to yield the A-isomer of Man8GlcNAc2 (Fig. 1) (4). Because of the Golgi apparatus location of the endomannosidase (14), glycoproteins with Glc1Man9GlcNAc2 that have escaped further glycosidic processing, but have been properly folded and exported from the ER, can be digested to enable Golgi-type processing (4).

Man9GlcNAc2-- The presence of this oligosaccharide, formed by glucosidase II digestion of Glc1Man9GlcNAc2, indicates that the glycoprotein in question should be inspected for exposure of hydrophobic surfaces not present in the native glycoprotein. If such surfaces are found, the oligosaccharide is enzymatically reglucosylated to regenerate Glc1Man9GlcNAc2 for an additional round of binding to CNX/CRT. Reglucosylation is carried out by a single remarkable ER resident enzyme, UDP-glucose:unfolded glycoprotein glucosyltransferase (3). The existence of this enzyme was originally suggested by reports of direct transfer of glucose from UDP-glucose to glycoproteins (15, 16). The product, Glc1Man9GlcNAc2, is the same structural isomer as that achieved by glucosidase II processing of Glc2Man9GlcNAc2 (17). Although Man9GlcNAc2 oligosaccharides on improperly folded glycoproteins are good substrates, Man9GlcNAc2 on properly folded glycoproteins and free Man9GlcNAc2 oligosaccharides are poor substrates for the glucosyltransferase. Thus, the enzyme has a catalytic site for glucose transfer and a separate site that interacts with non-native surfaces on glycoprotein folding intermediates. For some misfolded glycoproteins, several rounds of reglucosylation-deglucosylation can occur (3).

Man9GlcNAc2 is also the preferred oligosaccharide on coagulation factors V and VIII (18) and a cathepsin Z-related protein (19) needed for interactions with ERGIC-53, a lectin that is a resident of the ER-Golgi intermediate compartment and is involved in trafficking of these glycoproteins. In both cases interactions with ERGIC-53 were hindered by treatments with CSN but not with the ER mannosidase I inhibitor deoxymannojirimycin.

Man8GlcNAc2-- The presence of Man8GlcNAc2 on a misfolded glycoprotein indicates that it should be degraded. The B-isomer of Man8GlcNAc2 is generated by digestion of Man9GlcNAc2 by a kifunensine- and deoxymannojirimycin-sensitive ER mannosidase I (Fig. 1). For most glycoproteins digestion by ER mannosidase I is the last step in glycan processing before export to the Golgi apparatus and occurs at a time when folding and assembly should be complete. Abundant biochemical (Refs. 20 and 21, and references therein) and genetic (22) evidence implicates Man8GlcNAc2 in the degradation of many types of misfolded glycoproteins by cytoplasmic proteasomes, whereas properly folded glycoproteins bearing Man8GlcNAc2 escape degradation. Two models have been proposed, distinguished operationally by whether or not CNX binding stabilizes the glycoprotein. As first shown with myosin class I heavy chains (23) and subsequently with other systems (Refs. 20 and 21, and references therein), CNX binding stabilizes many misfolded glycoproteins. It has been suggested that degradation might involve interaction with a Man8GlcNAc2-specific lectin, which remains to be identified. This model is supported by the finding that misfolded carboxypeptidase Y bearing Man9GlcNAc2, Man7GlcNAc2, or Man6GlcNAc2 was more stable than with Man8GlcNAc2 (22). Degradation of misfolded variants of alpha 1-antitrypsin (AT) in hepatoma cells also requires formation of Man8GlcNAc2 (24). However, alpha 1-AT variants are destabilized by interaction with CNX. It has been proposed (24) that formation of Man8GlcNAc2-alpha 1-AT promotes CNX binding and accelerates degradation of alpha 1-AT because, after reglucosylation, Glc1Man8GlcNAc2-alpha 1-AT is predicted to be more resistant to glucosidase II digestion than Glc1Man9GlcNAc2-alpha 1-AT. This model is based upon the observation that the relative activity of glucosidase II toward free oligosaccharides is Glc1Man9GlcNAc > Glc1Man8GlcNAc > Glc1Man7GlcNAc (25). In the same study glucosidase II activity was found to be strongly influenced by the attachment of substrate oligosaccharides to protein. Thus, it would be interesting to extend these results with purified glucosidase II and purified glycoproteins bearing known Glc1ManxGlcNAc2 structural isomers. Recent studies have implicated Man7GlcNAc2, the ER mannosidase II product of Man8GlcNAc2, in a distinct mechanism involving nonproteasomal degradation of the alpha 1-AT variant PI Z (26).

    Endoplasmic Reticulum Oligosaccharide Quality Control
TOP
Oligosaccharides as Information...
Oligosaccharide-based...
Endoplasmic Reticulum...
Defective Synthesis or...
N-Linked Glycosylation as an...
Insights from Other Biological...
Summary and Perspectives
REFERENCES

The preceding section reviewed the role of N-linked Glc3Man9GlcNAc2 in quality control of nascent ER glycoproteins. Conversely, cells have several strategies for maintaining the quantity of Glc3Man9GlcNAc2-P-P-dolichol, the direct precursor of N-linked Glc3Man9GlcNAc2 (Fig. 2). Glc3Man9GlcNAc2-P-P-dolichol synthesis occurs in a stepwise manner from dolichol-P, requiring four donor substrates in this order: UDP-GlcNAc (2 eq), GDP-mannose (5 eq), mannose-P-dolichol (MPD; 4 eq), and glucose-P-dolichol (GPD; 3 eq). MPD and GPD are formed by transfer of mannose or glucose from GDP-mannose or UDP-glucose, respectively, to dolichol-P. Each sugar residue in Glc3Man9GlcNAc2-P-P-dolichol is added by a separate transferase (5). This section will review regulation of priming of dolichol-P by its conversion to GlcNAc-P-P-dolichol, extension of LLO intermediates, and transfer of Glc3Man9GlcNAc2 from its dolichol-P-P carrier to appropriate asparaginyl residues in proteins.


View larger version (20K):
[in this window]
[in a new window]
 
Fig. 2.   ER oligosaccharide quality control and the UPR. Concentrations of Glc3Man9GlcNAc2-protein needed for efficient quality control are maintained by priming of LLO synthesis, extension of LLO intermediates, and transfer of LLO to nascent proteins. Insufficient quality control because of inadequate Glc3Man9GlcNAc2-protein triggers the UPR. There is genetic (G) evidence for UPR control of all three aspects of LLO metabolism, as well as biochemical (B) evidence for UPR control of LLO extension. Adequate Glc3Man9GlcNAc2-protein production relieves ER stress and deactivates the UPR.

Priming and Extension-- LLO synthesis is primed by UDP-GlcNAc:dolichol-P GlcNAc-1-P transferase (GPT), which transfers GlcNAc-1-P from UDP-GlcNAc to dolichol-P to yield GlcNAc- P-P-dolichol (27). Tunicamycin (TN) is a selective inhibitor of GPT (27), although high concentrations also inhibit protein palmitoylation (28). Several forms of regulation of GPT have been reported (27). Considerable information is available for the stimulation of GPT in vitro by exogenously added MPD (29). Stimulation can be achieved with the physiological beta -isomer of MPD but not with the alpha -isomer (30) or with GPD (31). GlcNAc-P-P-dolichol was recently shown to stimulate MPD synthase in vitro (29). The reciprocal stimulations of GPT and MPD synthase by their products may help maintain a balance of LLO substrates; GlcNAc-P-P-dolichol is needed for priming, and MPD is needed for extension. The intriguing possibility remains that related regulatory relationships exist for GPD synthesis.

Priming is dependent upon the dolichol-P concentration because LLO synthesis in cultured cells is increased by supplementation with dolichol-P (27). The concentration of dolichol-P, also required for the MPD and GPD synthases and hence extension of LLO intermediates, is regulated in response to various biological stimuli associated with increased synthesis of N-linked glycoproteins by cis-isoprenyltransferase, the enzyme system catalyzing the chain elongation stage in de novo dolichol-P biosynthesis (32-34). cis-Isoprenyltransferase regulation is most likely at the level of mRNA synthesis, but direct transcriptional studies remain to be performed. LLO extension can also be controlled by the unfolded protein response (below) (35).

Oligosaccharide Transfer-- Oligosaccharide transfer from Glc3Man9GlcNAc2-P-P-dolichol to appropriate asparaginyl residues of nascent proteins is catalyzed by the enzyme oligosaccharyltransferase (5). Even under conditions where Glc3Man9GlcNAc2-P-P-dolichol represents a minor fraction of the steady-state LLO pool, the selectivity of oligosaccharyltransferase for Glc3Man9GlcNAc2-P-P-dolichol ensures that most nascent proteins will be modified with Glc3Man9GlcNAc2. As an example of the importance of oligosaccharyltransferase selectivity in quality control, studies from the author's laboratory with primary human dermal fibroblasts showed that if Glc3Man9GlcNAc2-P-P-dolichol was only 10% of the LLO pool, it still corresponded to essentially all of the transferred oligosaccharide (35). However, lower percentages resulted in transfer of incomplete oligosaccharide intermediates that caused an unfolded protein response (see below). Mechanisms also exist to eliminate excess Glc3Man9GlcNAc2-P-P-dolichol (36, 37).

    Defective Synthesis or Processing of ER Information-carrying Oligosaccharides Triggers the Unfolded Protein Response (UPR)
TOP
Oligosaccharides as Information...
Oligosaccharide-based...
Endoplasmic Reticulum...
Defective Synthesis or...
N-Linked Glycosylation as an...
Insights from Other Biological...
Summary and Perspectives
REFERENCES

Interference with protein folding, assembly, or misfolded protein degradation in the ER triggers multiple aspects of the UPR (38-40). The first UPR aspect to be established involves transcriptional activation of genes encoding ER lumen chaperones and enzymes involved in protein folding. Reports of transcriptional control now exist for many genes, including those needed for ER maintenance and ER-associated degradation (41, 42). UPR regulation of transcription occurs in all eukaryotes examined so far. A novel ER-to-nucleus signaling pathway in Saccharomyces cerevisiae has been elucidated, involving the ER transmembrane kinase Ire1p/Ern1p. Corresponding pathways in mammalian cells are more complex because at least two forms of Ire1p, alpha  (43) and beta  (44), and the transcription factor ATF6 (45) are involved. All three are synthesized as ER transmembrane proteins. There is no evidence for proteolytic processing of Ire1p in S. cerevisiae. By comparison, activation of the UPR in mammalian cells causes release of the cytoplasmic domains of the mammalian Ire1 proteins (46) and ATF6 (45) by "regulated intramembrane proteolysis" (47). The released cytoplasmic domains then enter the nucleus to facilitate transcription of mammalian UPR genes. The cytoplasmic domain of ATF6, which clearly becomes a transcription factor, is released by the site 1 and site 2 SREBP proteases (48), raising the interesting possibility of a relationship between sterol metabolism and the UPR. Mammalian cells with various presenilin-1 mutations have been reported to have impaired Ire1p function (46, 49), suggesting a potential role for presenilin-1 in Ire1p cleavage, although contradictory results have recently appeared (50). The cytoplasmic domains of the Ire1 proteins are bifunctional kinases-endonucleases that undergo autophosphorylation upon UPR activation. In S. cerevisiae the Ire1p endonuclease activity propagates the UPR by participating in splicing of the mRNA encoding the transcription factor Hac1p (51). A similar chain of events appears to occur in mammalian cells (46), although the endonuclease substrate remains to be identified.

Biochemical evidence exists for other UPR aspects in mammalian cells: (i) inhibition of translation because of phosphorylation of eIF2alpha by the transmembrane PKR-like ER-associated kinase "PERK" (52), (ii) apoptosis involving CHOP (53) and ER-associated caspase-12 (54), and (iii) enhanced extension of dolichol-linked oligosaccharide intermediates (35). Translational inhibition aids in resistance to ER stress (55) by lowering the load of misfolded protein and by allowing the selective expression of genes involved in amino acid metabolism (56). PERK is also responsible for cell cycle arrest due to the UPR (57). The mechanisms of activation for PERK and Ire1p by misfolded proteins are similar (58). Under normal conditions the lumenal domains of PERK and Ire1p interact dynamically with BiP. Misfolded proteins that accumulate in the ER lumen form complexes with BiP, lowering the amount of BiP available for interaction with Ire1p and PERK. In the absence of bound BiP, the lumenal domains dimerize. Consequently, the cytoplasmic kinase domains are brought into proximity, allowing autophosphorylation and activation of downstream events.

All aspects of the UPR can be caused by interference with the synthesis of N-linked oligosaccharides. (i) Inadvertent depletion of glucose from culture medium, associated with deficient protein glycosylation, led to the discovery of stress induction of GRP78 (BiP) and GRP94 as well as their designations as glucose-regulated proteins (59, 60). (ii) TN, which blocks protein N-glycosylation by inhibiting GPT, is a highly potent UPR inducer causing transcription of BiP, phosphorylation of eIF2alpha , inhibition of translation, and cell death. The effect of the UPR on the dolichol pathway cannot be studied with TN due to direct inhibition. Commercial TN preparations typically contain mixtures of homologues that block N-glycosylation but paradoxically vary in their abilities to inhibit translation (61). It remains to be determined whether these homologues also vary in other aspects of UPR activation. (iii) CSN, an inhibitor of ER glucosidases I and II, eliminates aspects of ER quality control requiring processing of asparagine-linked Glc3Man9GlcNAc2. CSN and other glucosidase inhibitors are less potent UPR inducers than TN, because their use does not cause inhibition of translation (62) or cell death (63). This suggests that the N-linked Glc3Man9GlcNAc2 oligosaccharide itself contributes to glycoprotein folding and assembly, perhaps by enhancing the hydrophilicity of folding intermediates. However, CSN treatment does activate BiP transcription and the dolichol pathway (35), confirming the importance of N-linked Glc0-2Man9GlcNAc2 in ER protein quality control. (iv) A selection for S. cerevisiae mutants with activated UPRs yielded cells with defects in genes required for N-glycosylation (64).

    N-Linked Glycosylation as an Aspect of UPR
TOP
Oligosaccharides as Information...
Oligosaccharide-based...
Endoplasmic Reticulum...
Defective Synthesis or...
N-Linked Glycosylation as an...
Insights from Other Biological...
Summary and Perspectives
REFERENCES

Screens for S. cerevisiae genes activated by the UPR not only revealed genes encoding various ER chaperones and enzymes involved in protein folding and assembly but also genes involved in other functions associated with ER maintenance including the synthesis and processing of Glc3Man9GlcNAc2-protein (Fig. 2) (41). This evidence is supported by biochemical studies from the author's laboratory (35). Activation of the UPR in primary cultures of adult dermal fibroblasts stimulated extension of LLO intermediates to Glc3Man9GlcNAc2-P-P-dolichol and increased the fraction of nascent ER proteins bearing Glc3Man9GlcNAc2. The metabolic step(s) in LLO synthesis activated by the UPR has yet to be identified.

    Insights from Other Biological Systems: Stable and Transient Forms of Oligosaccharide Information
TOP
Oligosaccharides as Information...
Oligosaccharide-based...
Endoplasmic Reticulum...
Defective Synthesis or...
N-Linked Glycosylation as an...
Insights from Other Biological...
Summary and Perspectives
REFERENCES

A survey of selected biological functions of oligosaccharides reveals that oligosaccharides can carry information by either of two modes, stable or transient. Oligosaccharides carrying stable information are not altered in the course of serving a biological role and are usually directly involved in the function of the molecule or cell to which they are attached or from which they originate. Examples include sialyl LewisX-like glycans bound by selectins (65), sialylconjugates recognized by siglecs (66), and sulfated GalNAc on glycoprotein hormones that interact with specific clearance receptors (67). Chitin-like Nod factors secreted by Rhizobia are recognized by specific receptors on the root hairs of legumes to promote nodulation (68, 69). Recently, Notch was shown to be modulated by its GlcNAcbeta 1,3Fuc O-glycan, formed by the glycosyltransferase activity of Fringe (70, 71).

In contrast, oligosaccharides that carry transient information undergo structural changes during the course of biological activity and may not necessarily be involved in the ultimate biological functions of the molecules or cells that bear them. Therefore, the critical modification might not be detected by biochemical analysis of the mature glycoconjugate. The glucose residues on N-linked oligosaccharides, which as noted by Spiro (4) are transient, are definitive examples. Another example is the lysosomal sorting signal mannose-6-P found on high mannose oligosaccharides of lysosomal enzymes, which is dephosphorylated once the lysosome has been reached (72). Monosaccharides can also carry information transiently. O-GlcNAc on cytoplasmic and nuclear proteins can be removed and replaced many times during the life of a protein (73).

    Summary and Perspectives
TOP
Oligosaccharides as Information...
Oligosaccharide-based...
Endoplasmic Reticulum...
Defective Synthesis or...
N-Linked Glycosylation as an...
Insights from Other Biological...
Summary and Perspectives
REFERENCES

This article attempted to demonstrate how oligosaccharides can carry biological information. The large variety of oligosaccharide structures that can be created by just a few glycosidically linked monosaccharides, and the potential for ionic as well as hydrogen bonds, makes them highly suitable for this purpose. In particular, novel oligosaccharides and oligosaccharide modifications are very likely to carry essential information and should never be ignored. Because they can perform so many functions, there is no way to predict how oligosaccharides may be involved in any particular biological system under study. For this reason, a fruitful area for future research will be the development of new reagents and techniques that can identify information-carrying oligosaccharides in action.

    ACKNOWLEDGEMENTS

I am especially grateful to Kazu Mori, Robert Spiro, Skip Waechter, Ann White, and David Williams, who provided excellent suggestions during the preparation of the article.

    FOOTNOTES

* This minireview will be reprinted in the 2001 Minireview Compendium, which will be available in December, 2001. Work in the author's laboratory is supported by National Institutes of Health Grant GM38545 and Welch Foundation Grant I-1168.

Dagger To whom correspondence should be addressed: Dept. of Pharmacology, UT-Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9041. Tel.: 214-648-2323; Fax: 214-648-8626; E-mail: mlehrm@ mednet.swmed.edu.

Published, JBC Papers in Press, January 26, 2001, DOI 10.1074/jbc.R100002200

2 The term "lectin-like chaperone" was originally introduced into the literature when the binding of CNX and CRT to glycoproteins was known to require specific oligosaccharide-dependent interactions, but the lectin activities for CNX and CRT remained to be demonstrated. Because the lectin activities of CNX and CRT have now been proven, the term "lectin-chaperone" will be used.

    ABBREVIATIONS

The abbreviations used are: ER, endoplasmic reticulum; AT, antitrypsin; CNX, calnexin; CRT, calreticulin; CSN, castanospermine; eIF, eukaryotic initiation factor; GPD, glucose-P-dolichol; GPT, GlcNAc-1-P transferase; GRP, glucose-regulated protein; LLO, lipid-linked oligosaccharide; MPD, mannose-P-dolichol; PERK, PKR-like ER kinase; TN, tunicamycin; UPR, unfolded protein response.

    REFERENCES
TOP
Oligosaccharides as Information...
Oligosaccharide-based...
Endoplasmic Reticulum...
Defective Synthesis or...
N-Linked Glycosylation as an...
Insights from Other Biological...
Summary and Perspectives
REFERENCES

1. Hassid, W. Z., and Ballou, C. E. (1957) in The Carbohydrates: Chemistry, Biochemistry, Physiology (Pigman, W., ed) , pp. 478-535, Academic Press, New York
2. Ellgaard, L., Molinari, M., and Helenius, A. (1999) Science 286, 1882-1888[Abstract/Free Full Text]
3. Parodi, A. J. (2000) Annu. Rev. Biochem. 69, 69-93[CrossRef][Medline] [Order article via Infotrieve]
4. Spiro, R. G. (2000) J. Biol. Chem. 275, 35657-35660[Free Full Text]
5. Varki, A., Cummings, R., Esko, J., Freeze, H., Hart, G., and Marth, J. (eds) (1999) Essentials of Glycobiology , Cold Spring Harbor Laboratory, Cold Spring Harbor, NY
6. Hubbard, S. C., and Robbins, P. W. (1979) J. Biol. Chem. 254, 4568-4576[Medline] [Order article via Infotrieve]
7. Hammond, C., Braakman, I., and Helenius, A. (1994) Proc. Natl. Acad. Sci. U. S. A. 91, 913-917[Abstract]
8. Ware, F. E., Vassilakos, A., Peterson, P. A., Jackson, M. R., Lehrman, M. A., and Williams, D. (1995) J. Biol. Chem. 270, 4697-4704[Abstract/Free Full Text]
9. Spiro, R. G., Zhu, Q., Bhoyroo, V., and Soling, H.-D. (1996) J. Biol. Chem. 271, 11588-11594[Abstract/Free Full Text]
10. Patil, A. R., Thomas, C. J., and Surolia, A. (2000) J. Biol. Chem. 275, 24348-24356[Abstract/Free Full Text]
11. Vassilakos, A., Michalak, M., Lehrman, M. A., and Williams, D. B. (1998) Biochemistry 37, 3480-3490[CrossRef][Medline] [Order article via Infotrieve]
12. Ihara, Y., Cohen-Doyle, M. F., Saito, Y., and Williams, D. B. (1999) Mol. Cell 4, 331-341[Medline] [Order article via Infotrieve]
13. Saito, Y., Ihara, Y., Leach, M. R., Cohen-Doyle, M. F., and Williams, D. B. (1999) EMBO J. 18, 6718-6729[Abstract/Free Full Text]
14. Zuber, C., Spiro, M. J., Guhl, B., Spiro, R. G., and Roth, J. (2000) Mol. Biol. Cell 11, 4227-4240[Abstract/Free Full Text]
15. Banerjee, D. K., Scher, M. G., and Waechter, C. J. (1981) Biochemistry 20, 1561-1568[Medline] [Order article via Infotrieve]
16. Parodi, A. J., Mendelzon, D. H., and Lederkremer, G. Z. (1983) J. Biol. Chem. 258, 8260-8265[Abstract/Free Full Text]
17. Trombetta, E. S., Bosch, M., and Parodi, A. J. (1989) Biochemistry 28, 8108-8116[Medline] [Order article via Infotrieve]
18. Moussalli, M., Pipe, S. W., Hauri, H.-P., Nichols, W. C., Ginsburg, D., and Kaufman, R. J. (1999) J. Biol. Chem. 274, 32539-32542[Abstract/Free Full Text]
19. Appenzeller, C., Andersson, H., Kappeler, F., and Hauri, H.-P. (1999) Nat. Cell Biol. 1, 330-334[CrossRef][Medline] [Order article via Infotrieve]
20. Chung, D. H., Ohashi, K., Watanabe, M., Miyasaka, N., and Hirosawa, S. (2000) J. Biol. Chem. 275, 4981-4987[Abstract/Free Full Text]
21. Wang, J., and White, A. L. (2000) Biochemistry 39, 8993-9000[CrossRef][Medline] [Order article via Infotrieve]
22. Jakob, C. A., Burda, P., Roth, J., and Aebi, M. (1998) J. Cell Biol. 142, 1223-1233[Abstract/Free Full Text]
23. Jackson, M. R., Cohen-Doyle, M. F., Peterson, P. A., and Williams, D. B. (1994) Science 263, 384-387[Medline] [Order article via Infotrieve]
24. Liu, Y., Choudhury, P., Cabral, C. M., and Sifers, R. N. (1999) J. Biol. Chem. 274, 5861-5867[Abstract/Free Full Text]
25. Grinna, L. S., and Robbins, P. W. (1980) J. Biol. Chem. 255, 2255-2258[Abstract/Free Full Text]
26. Cabral, C. M., Choudhury, P., Liu, Y., and Sifers, R. N. (2000) J. Biol. Chem. 275, 25015-25022[Abstract/Free Full Text]
27. Lehrman, M. A. (1991) Glycobiology 1, 553-562[Abstract]
28. Patterson, S. I., and Skene, J. H. P. (1994) J. Cell Biol. 124, 521-536[Abstract]
29. Kean, E. L., Wei, Z., Anderson, V. E., Zhang, N., and Sayre, L. (1999) J. Biol. Chem. 274, 34072-34082[Abstract/Free Full Text]
30. Kean, E. L., Rush, J. S., and Waechter, C. J. (1994) Biochemistry 33, 10508-10512[Medline] [Order article via Infotrieve]
31. Kean, E. L. (1985) J. Biol. Chem. 260, 12561-12571[Abstract/Free Full Text]
32. Crick, D. C., and Waechter, C. J. (1994) J. Neurochem. 62, 247-256[Medline] [Order article via Infotrieve]
33. Crick, D. C., Scocca, J. R., Rush, J. S., Frank, D. W., Krag, S. S., and Waechter, C. J. (1994) J. Biol. Chem. 269, 10559-10565[Abstract/Free Full Text]
34. Konrad, M., and Merz, W. E. (1996) Biochem. J. 316, 575-581[Medline] [Order article via Infotrieve]
35. Doerrler, W. T., and Lehrman, M. A. (1999) Proc. Natl. Acad. Sci. U. S. A. 96, 13050-13055[Abstract/Free Full Text]
36. Spiro, M. J., and Spiro, R. G. (1991) J. Biol. Chem. 266, 5311-5317[Abstract/Free Full Text]
37. Cacan, R., and Verbert, A. (2000) Glycobiology 10, 645-648[Abstract/Free Full Text]
38. Chapman, R., Sidrauski, C., and Walter, P. (1998) Annu. Rev. Cell Dev. Biol. 14, 459-485[CrossRef][Medline] [Order article via Infotrieve]
39. Kaufman, R. J. (1999) Genes Dev. 13, 1211-1233[Free Full Text]
40. Mori, K. (2000) Cell 101, 451-454[Medline] [Order article via Infotrieve]
41. Travers, K. J., Patil, C. K., Wodicka, L., Lockhart, D. J., Weissman, J. D., and Walter, P. (2000) Cell 101, 249-258[Medline] [Order article via Infotrieve]
42. Casagrande, R., Stern, P., Diehn, M., Shamu, C., Osario, M., Zuniga, M., Brown, P. O., and Ploegh, H. L. (2000) Mol. Cell 5, 729-735[Medline] [Order article via Infotrieve]
43. Tirasophon, W., Welihinda, A. A., and Kaufman, R. J. (1998) Genes Dev. 12, 1812-1824[Abstract/Free Full Text]
44. Wang, X. Z., Harding, H. P., Zhang, Y., Jolicoeur, E. M., Kuroda, M., and Ron, D. (1998) EMBO J. 17, 5708-5717[Abstract/Free Full Text]
45. Haze, K., Yoshida, H., Yanagi, H., Yura, T., and Mori, K. (1999) Mol. Biol. Cell 10, 3787-3799[Abstract/Free Full Text]
46. Niwa, M., Sidrauski, C., Kaufman, R. J., and Walter, P. (1999) Cell 99, 691-702[Medline] [Order article via Infotrieve]
47. Brown, M. S., Ye, J., Rawson, R. B., and Goldstein, J. L. (2000) Cell 100, 391-398[Medline] [Order article via Infotrieve]
48. Ye, J., Rawson, R. B., Komuro, R., Chen, X., Dave, U., Prywes, R., Brown, M. S., and Goldstein, J. L. (2000) Mol. Cell 6, 1355-1364[Medline] [Order article via Infotrieve]
49. Katayama, T., Imaizumi, K., Sato, N., Miyoshi, K., Kudo, T., Hitomi, J., Morihara, T., Yoneda, T., Gomi, F., Mori, Y., Nakano, Y., Takeda, J., Tsuda, T., Itoyama, Y., Murayama, O., Takashima, A., St. George-Hyslop, P., Takeda, M., and Tohyama, M. (1999) Nat. Cell Biol. 1, 479-485[CrossRef][Medline] [Order article via Infotrieve]
50. Sato, N., Urano, F., Leem, J. Y., Kim, S.-H., Li, M., Donoviel, D., Bernstein, A., Lee, A. S., Ron, D., Veselits, M. L., Sisodia, S. S., and Thinakaran, G. (2000) Nat. Cell Biol. 2, 863-870[CrossRef][Medline] [Order article via Infotrieve]
51. Sidrauski, C., and Walter, P. (1997) Cell 90, 1031-1039[Medline] [Order article via Infotrieve]
52. Harding, H. P., Zhang, Y., and Ron, D. (1999) Nature 397, 271-274[CrossRef][Medline] [Order article via Infotrieve]
53. Zinszner, H., Kuroda, M., Wang, X., Batchvarova, N., Lightfoot, R. T., Remotti, H., Stevens, J. L., and Ron, D. (1998) Genes Dev. 12, 982-995[Abstract/Free Full Text]
54. Nakagawa, T., Zhu, H., Morishima, N., Li, E., Xu, J., Yanker, B. A., and Yuan, J. (2000) Nature 403, 98-103[CrossRef][Medline] [Order article via Infotrieve]
55. Harding, H. P., Zhang, Y., Bertolotti, A., Zeng, H., and Ron, D. (2000) Mol. Cell 5, 897-904[CrossRef][Medline] [Order article via Infotrieve]
56. Harding, H. P., Novoa, I., Zhang, Y., Zeng, H., Wek, R., Schapira, M., and Ron, D. (2000) Mol. Cell 6, 1099-1108[Medline] [Order article via Infotrieve]
57. Brewer, J. W., and Diehl, J. A. (2000) Proc. Natl. Acad. Sci. U. S. A. 97, 12625-12630[Abstract/Free Full Text]
58. Bertolotti, A., Zhang, Y., Hendershot, L. M., Harding, H. P., and Ron, D. (2000) Nat. Cell Biol. 2, 326-332[CrossRef][Medline] [Order article via Infotrieve]
59. Pouyssegur, J., Shiu, R. P., and Pastan, I. (1977) Cell 11, 941-947[Medline] [Order article via Infotrieve]
60. Shiu, R. P., Pouyssegur, J., and Pastan, I. (1977) Proc. Natl. Acad. Sci. U. S. A. 74, 3840-3844[Abstract]
61. Duksin, D., and Mahoney, W. C. (1982) J. Biol. Chem. 257, 3105-3109[Abstract/Free Full Text]
62. Brostrom, C. O., and Brostrom, M. A. (1998) in Progress in Nucleic Acid Research and Molecular Biology (Moldave, K., ed) , pp. 79-125, Academic Press, New York
63. Lehrman, M. A., and Zeng, Y. (1989) J. Biol. Chem. 264, 1584-1593[Abstract/Free Full Text]
64. Ng, D. T. W., Spear, E. D., and Walter, P. (2000) J. Cell Biol. 150, 77-88[Abstract/Free Full Text]
65. McEver, R. P., and Cummings, R. D. (1997) J. Clin. Invest. 100, 485-492[Free Full Text]
66. Munday, J., Floyd, H., and Crocker, P. R. (1999) J. Leukocyte Biol. 66, 705-711[Abstract]
67. Roseman, D. S., and Baenziger, J. U. (2000) Proc. Natl. Acad. Sci. U. S. A. 97, 9949-9954[Abstract/Free Full Text]
68. Etzler, M. (1998) J. Cell. Biochem. Suppl. 30/31, 123-128
69. Etzler, M., Kalsi, G., Ewing, N. N., Roberts, N. J., Day, R. B., and Murphy, J. B. (1999) Proc. Natl. Acad. Sci. U. S. A. 96, 5856-5861[Abstract/Free Full Text]
70. Moloney, D. L., Panin, V. M., Johnston, S. H., Chen, J., Shao, L., Wilson, R., Wang, Y., Stanley, P., Irvine, K. D., Haltiwanger, R. S., and Vogt, T. F. (2000) Nature 406, 369-375[CrossRef][Medline] [Order article via Infotrieve]
71. Bruckner, K., Perez, L., Clausen, H., and Cohen, S. (2000) Nature 406, 411-415[CrossRef][Medline] [Order article via Infotrieve]
72. Kornfeld, S. (1986) J. Clin. Invest. 77, 1-6[Medline] [Order article via Infotrieve]
73. Hart, G. W. (1997) Annu. Rev. Biochem. 66, 315-335[CrossRef][Medline] [Order article via Infotrieve]


Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.