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

endoplasmic reticulum antitrypsin calnexin calreticulin castanospermine eukaryotic initiation factor glucose-P-dolichol GlcNAc-1-P transferase glucose-regulated protein lipid-linked oligosaccharide mannose-P-dolichol PKR-like ER kinase tunicamycin unfolded protein response 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 α or β glycosidic linkages of their hydroxyls to form oligosaccharides (with relatively few sugars) and polysaccharides (with many sugars) (1Hassid W.Z. Ballou C.E. Pigman W. The Carbohydrates: Chemistry, Biochemistry, Physiology. Academic Press, New York1957: 478-535Crossref Google Scholar). 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 β1,4-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 termedaglycones that themselves are not carbohydrates, but typically are proteins or lipids, and whose biological properties can be dramatically changed by the oligosaccharide. 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 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 (2Ellgaard L. Molinari M. Helenius A. Science. 1999; 286: 1882-1888Crossref PubMed Scopus (1064) Google Scholar). Fig. 1 summarizes the five commonN-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 (3Parodi A.J. Annu. Rev. Biochem. 2000; 69: 69-93Crossref PubMed Scopus (536) Google Scholar) and Spiro (4Spiro R.G. J. Biol. Chem. 2000; 275: 35657-35660Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar). 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 (5Varki A. Cummings R. Esko J. Freeze H. Hart G. Marth J. Essentials of Glycobiology. Cold Spring Harbor Laboratory, Cold Spring Harbor, NY1999Google Scholar).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 (4Spiro R.G. J. Biol. Chem. 2000; 275: 35657-35660Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar), no specific function or informational content has been reported for Glc3Man9GlcNAc2 on glycoproteins, although its hydrophilic character promotes protein folding (see below). With a half-time of less than 2 min (6Hubbard S.C. Robbins P.W. J. Biol. Chem. 1979; 254: 4568-4576Abstract Full Text PDF PubMed Google Scholar) 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. The presence of this oligosaccharide indicates that the protein to which it is attached is ready to interact with a lectin-chaperone, 2The 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. 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 (6Hubbard S.C. Robbins P.W. J. Biol. Chem. 1979; 254: 4568-4576Abstract Full Text PDF PubMed Google Scholar) 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 (3Parodi A.J. Annu. Rev. Biochem. 2000; 69: 69-93Crossref PubMed Scopus (536) Google Scholar, 4Spiro R.G. J. Biol. Chem. 2000; 275: 35657-35660Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar, 7Hammond C. Braakman I. Helenius A. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 913-917Crossref PubMed Scopus (719) Google Scholar). CNX (8Ware F.E. Vassilakos A. Peterson P.A. Jackson M.R. Lehrman M.A. Williams D. J. Biol. Chem. 1995; 270: 4697-4704Abstract Full Text Full Text PDF PubMed Scopus (382) Google Scholar) and CRT (9Spiro R.G. Zhu Q. Bhoyroo V. Soling H.-D. J. Biol. Chem. 1996; 271: 11588-11594Abstract Full Text Full Text PDF PubMed Scopus (259) Google Scholar) 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 × 105m−1 (10Patil A.R. Thomas C.J. Surolia A. J. Biol. Chem. 2000; 275: 24348-24356Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar). Glc1Man(5–9)GlcNAc2, but not Glc1Man4GlcNAc2, bind to CNX (11Vassilakos A. Michalak M. Lehrman M.A. Williams D.B. Biochemistry. 1998; 37: 3480-3490Crossref PubMed Scopus (228) Google Scholar) and CRT (9Spiro R.G. Zhu Q. Bhoyroo V. Soling H.-D. J. Biol. Chem. 1996; 271: 11588-11594Abstract Full Text Full Text PDF PubMed Scopus (259) Google Scholar), and the three mannosyl residues that form the “arm” to which glucose is attached also contribute to binding (11Vassilakos A. Michalak M. Lehrman M.A. Williams D.B. Biochemistry. 1998; 37: 3480-3490Crossref PubMed Scopus (228) Google Scholar). Because only oligosaccharides with a single α-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 (12Ihara Y. Cohen-Doyle M.F. Saito Y. Williams D.B. Mol. Cell. 1999; 4: 331-341Abstract Full Text Full Text PDF PubMed Scopus (150) Google Scholar) and CRT (13Saito Y. Ihara Y. Leach M.R. Cohen-Doyle M.F. Williams D.B. EMBO J. 1999; 18: 6718-6729Crossref PubMed Scopus (218) Google Scholar) 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 (3Parodi A.J. Annu. Rev. Biochem. 2000; 69: 69-93Crossref PubMed Scopus (536) Google Scholar, 8Ware F.E. Vassilakos A. Peterson P.A. Jackson M.R. Lehrman M.A. Williams D. J. Biol. Chem. 1995; 270: 4697-4704Abstract Full Text Full Text PDF PubMed Scopus (382) Google Scholar). 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 (3Parodi A.J. Annu. Rev. Biochem. 2000; 69: 69-93Crossref PubMed Scopus (536) Google Scholar). The situation has been complicated further by reports of some “lectin-only” and “lectin-independent” complexes of glycoprotein folding intermediates with CNX (3Parodi A.J. Annu. Rev. Biochem. 2000; 69: 69-93Crossref PubMed Scopus (536) Google Scholar). 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 Glcα1,3Man disaccharide to yield the A-isomer of Man8GlcNAc2 (Fig. 1) (4Spiro R.G. J. Biol. Chem. 2000; 275: 35657-35660Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar). Because of the Golgi apparatus location of the endomannosidase (14Zuber C. Spiro M.J. Guhl B. Spiro R.G. Roth J. Mol. Biol. Cell. 2000; 11: 4227-4240Crossref PubMed Scopus (85) Google Scholar), 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 (4Spiro R.G. J. Biol. Chem. 2000; 275: 35657-35660Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar). 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 (3Parodi A.J. Annu. Rev. Biochem. 2000; 69: 69-93Crossref PubMed Scopus (536) Google Scholar). The existence of this enzyme was originally suggested by reports of direct transfer of glucose from UDP-glucose to glycoproteins (15Banerjee D.K. Scher M.G. Waechter C.J. Biochemistry. 1981; 20: 1561-1568Crossref PubMed Scopus (49) Google Scholar, 16Parodi A.J. Mendelzon D.H. Lederkremer G.Z. J. Biol. Chem. 1983; 258: 8260-8265Abstract Full Text PDF PubMed Google Scholar). The product, Glc1Man9GlcNAc2, is the same structural isomer as that achieved by glucosidase II processing of Glc2Man9GlcNAc2 (17Trombetta E.S. Bosch M. Parodi A.J. Biochemistry. 1989; 28: 8108-8116Crossref PubMed Scopus (137) Google Scholar). 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 (3Parodi A.J. Annu. Rev. Biochem. 2000; 69: 69-93Crossref PubMed Scopus (536) Google Scholar). Man9GlcNAc2 is also the preferred oligosaccharide on coagulation factors V and VIII (18Moussalli M. Pipe S.W. Hauri H.-P. Nichols W.C. Ginsburg D. Kaufman R.J. J. Biol. Chem. 1999; 274: 32539-32542Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar) and a cathepsin Z-related protein (19Appenzeller C. Andersson H. Kappeler F. Hauri H.-P. Nat. Cell Biol. 1999; 1: 330-334Crossref PubMed Scopus (273) Google Scholar) 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. 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. 20Chung D.H. Ohashi K. Watanabe M. Miyasaka N. Hirosawa S. J. Biol. Chem. 2000; 275: 4981-4987Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar and 21Wang J. White A.L. Biochemistry. 2000; 39: 8993-9000Crossref PubMed Scopus (28) Google Scholar, and references therein) and genetic (22Jakob C.A. Burda P. Roth J. Aebi M. J. Cell Biol. 1998; 142: 1223-1233Crossref PubMed Scopus (303) Google Scholar) 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 I M.R. Cohen-Doyle M.F. 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A. 1999; PubMed Scopus Google Scholar). of the in of of intermediates to Glc3Man9GlcNAc2-P-P-dolichol and the of nascent ER proteins bearing The in by the has to be of biological of oligosaccharides that oligosaccharides can carry information by of or Oligosaccharides information are not altered in the of a biological role and are usually directly involved in the function of the or to which they are attached or from which they by Cummings J. PubMed Google Scholar), by J. H. J. Biol. 1999; PubMed Scopus Google Scholar), and on glycoprotein that interact with specific Proc. Natl. Acad. Sci. U. S. A. 2000; PubMed Scopus Google Scholar). factors by are by specific on the of to promote M. J. Cell. Biochem. 1998; Google Scholar, M. G. Proc. Natl. Acad. Sci. U. S. A. 1999; PubMed Scopus Google Scholar). was shown to be by its formed by the J. L. R. Y. P. 2000; PubMed Scopus Google Scholar, K. L. H. S. 2000; PubMed Scopus Google Scholar). In oligosaccharides that carry information structural during the of biological and may not necessarily be involved in the biological of the or that the not be by biochemical of the The glucose residues on N-linked which as by Spiro (4Spiro R.G. J. Biol. Chem. 2000; 275: 35657-35660Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar) are are example is the found on mannose oligosaccharides of which is the has been S. J. PubMed Scopus Google Scholar). can also carry information on cytoplasmic and proteins can be and many during the of a protein Annu. Rev. Biochem. PubMed Scopus Google Scholar). This to oligosaccharides can carry biological information. The of oligosaccharide structures that can be by a few linked and the for as well as hydrogen for this In oligosaccharides and oligosaccharide are likely to carry essential information and should be Because they can many there is no to oligosaccharides may be involved in biological For this a for will be the of and that can information-carrying oligosaccharides in I to and excellent during the of the