N-linked carbohydrates act as lumenal maturation and quality control protein tags

Ellgaard, L., Molinari, M., and Helenius, A. (1999) Setting the standards: quality control in the secretory pathway. Science 286, 1882–1888. Arvan, P., Zhao, X., Ramos-Castaneda, J., and Chang, A. (2002) Secretory pathway quality control operating in the Golgi, plasmalemmal, and endosomal systems. Traffic 3, 771–780. Taylor, ME, and Drickamer, K. (2003) Introduction to Glycobiology, Oxford University Press, Oxford. Rudd, P. M., Elliott, T., Cresswell, P., Wilson, I. A., and Dwek, R. A. (2001) Glycosylation and the immune system. Science 291, 2370–2376. Dennis, J. W. (1991) N-linked oligosaccharide processing and tumor cell biology. Sem. Cancer Biol. 2, 411–420. Kawamura, N., Ookawara, T., Suzuki, K., Konishi, K., Mino, M., and Taniguchi, N. (1992) Increased glycated Cu,Zn-superoxide dismutase levels in erythrocytes of patients with insulin-dependent diabetis mellitus. J. Clin. Endocrin. Met. 74, 1352–1354. Dennis, R. W., Granovsky, M., and Warren, C. E. (1999) Glycoprotein glycosylation and cancer progression. Biochim. Biophys. Acta 1473, 21–34. Ulsemer, P., Lanza, F., Baas, M. J., et L. (2000) Role of the leucine-rich domain of platelet GPIb-alpha in correct post-translational processing—the Nancy I Bernard-Soulier mutation expressed on CHO cells. Thromb. Haemost. 84, 104–111. Van Geet, C., Jaeken, J., Freson, K., et al. (2001) Congenital disorders of glycosylation type Ia and IIa are associated with different primary haemostatic complications. J. Inherit. Metab. Dis. 24, 477–492. Helenius, A. and Aebi, M. (2001) Intracellular functions of N-linked glycans. Science 291, 2364–2369. Silberstein, S. and Gilmore, R. (1996) Biochemistry, molecular biology, and genetics of the oligosaccharyltransferase. FASEB J. 10, 849–858. Nilsson, I., Kelleher, D. J., Miao, Y., et al. (2003) Photocross-linking of nascent chains to the STT3 subunit of the oligosaccharyltransferase complex. J. Cell Biol. 161, 715–725. Trombetta, E. S., Simons, J. F., and Helenius, A. (1996) Endoplasmic reticulum glucosidase II is composed of a catalytic subunit, conserved from yeast to mammals, and a tightly bound non-catalytic HDEL-containing subunit. J. Biol. Chem. 271, 27,509–27,516. Ou, W.-J., Cameron, P. H., Thomas, D. Y., and Bergeron, J. J. M. (1993) Association of folding intermediates of glycoproteins with calnexin during protein maturation. Nature 364, 771–776. Hammond, C. and Helenius, A. (1993) A chaperone with a sweet tooth. Curr. Biol. 3, 884–885. Hebert, D. N., Foellmer, B., and Helenius, A. (1995) Glucose trimming and reglucosylation determines glycoprotein association with calnexin. Cell 81, 425–433. Peterson, J. R., Ora, A., Nguyen Van., P., and Helenius, A. (1995) Transient, lectin-like association of calreticulin with folding intermediates of cellular and viral glycoproteins. Mol. Biol. Cell 6, 1173–1184. Chen, W., Helenius, J., Braakman, I., and Helenius, A. (1995) Cotranslational folding and calnexin binding of influenza hemagglutinin in the endoplasmic reticulum. Proc. Natl. Acad. Sci. USA 92, 6229–6233. Caramelo, J. J., Castro, O. A., Alonso, L. G., de Prat-Gay, G., and Parodi, A. J. (2003) UDP-Glc: glycoprotein glucosyltransferase recognizes structured and solvent accessible hydrophobic patches in molten globule-like folding intermediates. Proc. Natl. Acad. Acad. Sci. USA 100, 86–91. Sousa, M. and Parodi, A. J. (1995) The molecular basis for the recognition of misfolded glycoproteins by the UDP-Glc: glycoprotein glucosyltransferase. EMBO J. 14, 4196–4203. Trombetta, E.S. and Helenius, A. (2000) Conformational requirements for glycoprotein reglucosylation in the endoplasmic reticulum. J Cell. Biol. 148, 1123–1129. Gonzalez, D. S., Karaveg, K., Vandershall-Nairn, A. S., Lal, A., and Moreman, K. (1999) Identification, expression and characterization of a cDNA encoding human endoplasmic reticulum mannosidase I, the enzyme that catalyzes the first mannose trimming step in the mammalian Asn-linked oligosaccharide biosynthesis. J. Biol. Chem. 274, 21,375–21,386. Weng, S. and Spiro, R. (1996) Endoplasmic reticulum kifunensine-resistant alpha-mannosidase is enzymatically and immunologically related to the cytosolic alpha-mannosidase. Arch. Biochem. Biophys. 325, 113–123. Jakob, C. A., Burda, P., Roth, J., and Aebi, M. (1998) Degradation of misfolded endoplasmic reticulum glycoproteins in Saccharomyces cerevisiae is determined by a specific oligosaccharide structure. J Cell Biol. 142, 1223–1233. Liu, Y., Choudhury, P., Cabral, C. M., and Sifers, R. N. (1999) Oligosaccharide modification in the early secretory pathway directs the selection of a misfolded glycoprotein for degradation by the proteasome. J. Biol. Chem. 274, 5861–5867. Kornfeld, R. and Kornfeld, S. (1985) Assembly of asparagine-linked oligosaccharides. Annu. Rev. Biochem. 54, 631–664. Rabouille, C. and Spiro, R. (1992) Nonselective utilization of the endomannosidase pathway for processing glycoproteins by human hepatoma (HepG2) cells. J. Biol. Chem. 267, 11,573–11,578. Parlati, F., Dignard, D., Bergeron, J. J., and Thomas, D. Y. (1995) The calnexin homologue cnx1+ in Schizosaccharomyces pombe, is an essential gene which can be complemented by its soluble ER domain. EMBO J. 14, 3064–3072. Parlati, F., Dominguez, M., Bergeron, J. J. M., and Thomas, D. Y. (1995) Saccharomyces cerevisiae CNE1 encodes an endoplasmic reticulum (ER) membrane protein with sequence similarity to calnexin and calreticulin and functions as a constituent of the ER quality control apparatus. J. Biol. Chem. 270, 244–253. Jannatipour, M. and Rokeach, L. A. (1995) The schitzosaccharomyces pombe homologue of the chaperone calnexin is essential for viability. J. Biol. Chem. 270, 4845–4853. Mesaeli, N., Nakamura, K., Zvaritch, E., et al. (1999) Calreticulin is essential for cardiac development. J. Cell Biol. 144, 857–868. Schrag, J. D., Bergeron, J. J. M., Li, Y., et al. (2001) The structure of calnexin, an ER chaperone involved in quality control of protein folding. Mol. Cell 8, 633–644. Kapoor, M., Srinivas, H., Kandiah, E., et al. (2003) Interactions of substrate with calreticulin, an endoplasmic reticulum chaperone. J. Biol. Chem. 278, 6194–6200. Saito, Y., Ihara, Y., Leach, M. R., Cohen-Doyle, M. F., and Williams, D. B. (1999) Calreticulin functions in vitro as a molecular chaperone for both glycosylated and non-glycosylated proteins. EMBO J. 18, 6718–6729. Leach, M. R., Cohen-Doyle, M. F., Thomas, D. Y., and Williams, D. B. (2002) Localization of the lectin, ERp57 binding and polypeptide binding sites of calnexin and calreticulin. J. Biol. Chem. 277, 29,686–29,697. Ellgaard, L., Riek, R., Herrmann, T., Guntert, P., Braun, D., Helenius, A., and Wuthrich, K. (2001) NMR structure of the calreticulin P-domain. Proc. Natl. Acad. Sci. USA 98, 3133–3138. Frickel, E. M., Riek, R., Jelesarov, I., Helenius, A., Wuthrich, K., and Ellgaard, L. (2002) TROSY-NMR reveals interaction between ERp57 and the tip of the calreticulin P-domain. Proc. Natl. Acad. Sci. USA 99, 1954–1959. Hammond, C., Braakman, I., and Helenius, A. (1994) Role of N-linked oligosaccharides, glucose trimming and calnexin during glycoprotein folding in the endoplasmic reticulum. Proc. Natl. Acad. Sci. USA 91, 913–917. Hebert, D. N., Zhang, J.-X., Chen, W., Foellmer, B., and Helenius, A. (1997) The number and location of glycans on influenza hemagglutinin determine folding and association with calnexin and calreticulin. J. Cell Biol. 139, 613–623. Molinari, M. and Helenius, A. (2000) Chaperone selection during glycoprotein translocation into the endoplasmic reticulum. Science 288, 331–333. Daniels, R., Kurowski, B., Johnson, A. E., and Hebert, D. N. (2003) N-linked glycan direct the cotranslational maturation of influenza hemagglutinin. Mol. Cell 11, 79–90. Bukau, B. and Horwich, A. L. (1998) The hsp70 and hsp60 chaperone machines. Cell 92, 351–366. Hebert, D. N., Foellmer, B., and Helenius, A. (1996) Calnexin and calreticulin promote folding, delay oligomerization and suppress degradation of influenza hemagglutinin in microsomes. EMBO J. 15, 2961–2968. Vassilakos, A., Cohen-Doyle, M. F., Peterson, P. A., Jackson, M. R., and Williams, D. B. (1996) The molecular chaperone calnexin facilitates folding and assembly of class I histocompatibility molecules. EMBO J. 15, 1495–1506. Ora, A. and Helenius, A. (1995) Calnexin fails to associate with substrate proteins in glucosidase-deficient cell lines. J. Biol. Chem. 270, 26,060–26,062. Labriola, C., Cazzulo, J. J., and Parodi, A. J. (1995) Retention of glucose units added by the UDP-Glc:glycoprotein glucosyltrans-ferase delayes exit of glycoporteins from the endoplasmic reticulum. J. Cell Biol. 130, 771–779. Oliver, J. D., van, der, Wal, E. J., Bulleid, N. J., and High, S. (1997) Interaction of the thiol-dependent reductase ERp57 with nascent glycoproteins. Science 275, 86–88. Oliver, J. D., Roderick, H. L., Llewellyn, D. H., and High, S. (1999) ERp57 functions as a subunit of specific complexes formed with the ER lectins calreticulin and calnexin. Mol. Biol. Cell 10, 2573–2582. Van der Wal, F. J., Oliver, J. D., and High, S. (1998) The transient association of ERp57 with N-glycosylated proteins is regulated by glucose trimming. Eur. J. Biochem. 256, 51–59. Freedman, R. B., Klappa, P., and Ruddock, L. W. (2002) Protein disulfide isomerase exploit synergy between catalytic and specific binding domains. EMBO Rep. 3, 136–140. Srivastava, S. P., Fuchs, J. A., and Holtzman, J. L. (1993) The reported cDNA sequence for phospholipase C alpha encodes protein disulfide isomerase, isozyme Q-2 and not phospholipase C. Biochem. Biophys. Res. Commun. 193, 971–978. Bourdi, M., Demady, D., Martin, J. L., et al. (1995) cDNA cloning and baculovirus expression of the human liver endoplasmic retculum p58: characterization as a protein disulfide isomerase isoform, but not as a protease or a carnitine acyltransferase. Arch. Biochem. Biophys. 323, 397–403. Hirano, N., Shibasaki, F., Sakai, R., et al. (1995) Molecular cloning of the human glucose-regulated protein ERp57/GRP58, a thiol-dependent reductase. Eur. J. Biochem. 234, 336–342. Bonfils, C. (1998) Purification of a 58-kDa protein (ER58) from monkey liver microsomes and comparison with protein-disulfide isomerase. Eur. J. Biochem. 254, 420–427. Zapun, A., Darby, N. J., Tessier, D. C., Michalak, M., Bergeron, J. J. M., and Thomas, D. Y. (1998) Enhanced catalysis of ribonuclease B folding by the interaction of calnexin or calreticulin with ERp57. J. Biol. Chem. 273, 6009–6012. Antoniou, A. N., Ford, S., Alphey, M., Osborne, A., Elliot, T., and Powis, S. J. (2002) The oxidoreductase ERp57 efficiently reduces partially folded in preference to fully folded MHC class I molecules. EMBO J. 21, 2655–2663. Helenius, A. (1994) How N-linked oligosaccharides affect glycoprotein folding in the endoplasmic reticulum. Mol. Biol. Cell 5, 253–265. Parodi, A. J. (1999) Reglucosylation of glycoproteins and quality control of glycoprotein folding in the endoplasmic reticulum of yeast cells. Biochim. Biophys. Acta 1426, 287–295. Guerin, M. and Parodi, A. J. (2003) The UDP-glucose:glycoprotein glucosyltransferase is organized in at least two tightly bound domains from yeast to mammals. J. Biol. Chem. 278, 20,540–20,546. Trombetta, S. E. and Parodi, A. J. (1992) Purification to apparent homogeneity and partial characterization of rat liver UDP-glucose:glycoprotein glucosyltransferase. J. Biol. Chem. 267, 9236–9240. Ritter, C. and Helenius, A. (2000) Recognition of local glycoprotein misfolding by the ER folding sensor UDP-glucose:glycoprotein glucosyltransferase. Nature Struct. Biol. 7, 278–280. Taylor, S. C., Thibault, P., Tessier, D. C. M., Bergeron, J. J. M., and Thomas, D. Y. (2003) Glycopeptide specificity of the secretory protein folding sensor UDP-glucose glycoprotein:glucosyltransferse. EMBO Rep. 4, 405–411. Fanchiotti, S., Fernandez, F., D'Alessio, C., and Parodi, A. J. (1998) The UDP-glc:glycoprotein glucosyltransferase is essential for Schizosaccharomyces pombe viability under conditions of extreme endoplasmic retculum stress. J. Cell Biol. 143, 625–635. Fernandez, F. S., Trombetta, S. E., Hellman, U., and Parodi, A. J. (1994) Purification to homogeneity of UDP-glucose:glycoprotein glucosyltransferase from Schizosaccharomyces pombe and apparent absence of the enzyme from Saccharomyces cerevisae. J. Biol. Chem. 269, 30,701–30,706. Zhang, J.-X., Braakman, I., Matlack, K. E. S., and Helenius, A. (1997) Quality control in the secretory pathway: the role of calreticulin, calnexin and BiP in the retention of glycoproteins with C-terminal truncations. Mol. Biol. Cell 8, 1943–1954. Elliott, JG, Oliver, JD, and High, S (1997) The thiol-dependent reductase ERp57 interacts specifically with N-glycosylated integral membrane proteins. J Biol. Chem. 272, 13849–13855. Kang, S. J. and Cresswell, P. (2002) Calnexin, calreticulin and ERp57 cooperate in disulfide bond formation in human CD1d heavy chain. J. Biol. Chem. 277, 44,838–44,844. Rothman, J. E. (1987) Protein sorting by selective retention in the endoplasmic reticulum and Golgi stack. Cell 50, 521–522. Hurtley, S. M. and Helenius, A. (1989) Protein oligomerization in the endoplasmic reticulum. Annu. Rev. Cell Biol. 5, 277–307. Nishimura, N., Bannykh, S., Slabough, S., et al. (1999) A di-acidic (DXE) code directs concentration of cargo during export from the endoplasmic reticulum. J. Biol. Chem. 274, 15,937–15,946. Ma, Y. and Hendershot, L. M. (2001) The unfolded tale of the unfolded protein response. Cell 107, 827–830. Schrag, J. D., Propopio, D. O., Cygler, M., Thomas, D. Y., and Bergeron, J. J. M. (2003) Lectin control of protein folding and sorting in the secretory pathway. Trends Biochem. Sci. 28, 49–57. Hauri, H. P., Appenzeller, C., Kuhn, F., and Nufer, O. (2000) Lectins and traffic in the secretory pathway. FEBS Lett. 476, 32,539–32,542. Moussali, M., Pipe, S. W., Hauri, H. P., et al (1999) Mannose-dependent endoplasmic reticulum (ER)-Golgi intermediate compartment-53 mediated ER to Golgi trafficking of coagulation factors V and VIII. J. Biol. Chem. 274, 32,539–32,542. Appenzeller, C., Andersson, H., Kappeler, F., and Hauri, H.-P. (1999) The lectin ERGIC-53 is a cargo transport receptor for glycoproteins. Nature Cell Biol 1, 330–334. Schubert, U., Anton, L. C., Gibbs, J., Norbury, C. C., Yewdell, J. W., and Bennink, J. R. (2000) Rapid degradation of a large fraction of newly synthesized proteins by proteasomes. Nature 404, 770–774. Kopito, R. R. (1997) ER quality control:the cytoplasmic connection. Cell 88, 427–430. Bonifacino, J. S. and Weissman, A. M. (1998) Ubiquitin and the control of protein fate in the secretory and endocytic pathways. Annu. Rev. Cell Dev. Biol. 14, 19–57. Pelham, H. R. B. (1989) Control of protein exit from the endoplasmic reticulum. Annu. Rev. Cell Biol. 5, 1–23. Jackson, M. R., Nilsson, T., and Peterson, P. A. (1993) Retrieval of transmembrane proteins to the endoplasmic reticulum. J. Cell Biol. 121, 317–333. Rajagopalan, S., Xu, Y., and Brenner, M. B. (1994) Retention of unassembled components of integral membrane proteins by calnexin. Science 263, 387–390. Sitia, R., Neuberger, M., Alberini, C., et al. (1990) Developmental regulation of IgM secretion: the role of the carboxy-terminal cysteine. Cell 60, 781–790. Su, K., Stoller, T., Rocco, J., Zemsky, J., and Green, R. (1993) Pre-Golgi degradation of yeast prepro-a-factor in a mammalian cell. J. Biol. Chem. 268, 14,301–14,309. Yang, M., Omura, S., Bonifacino, J. S., and Weissman, A. M. (1998) Novel aspects of degradation of T cell receptor subunits from the endoplasmic reticulum (ER) in T cells: importance of oligosaccharide processing, ubiquitination and proteasome-dependent removal from ER membranes. J. Exp. Med. 187, 835–846. Cabral, C. M., Liu, Y., and Sifers, R. N. (2001) Dissecting glycoprotein quality control in the secretory pathway. Trends Biochem. Sci. 26, 619–624. Fewell, S. W., Travers, K. J., Weissman, J. S., and Brodsky, J. L. (2001) The action of molecular chaperones in the early secretory pathway. Annu. Rev. Genet. 35, 149–191. McCracken, A. A. and Brodsky, J. L. (1996) Assembly of ER-associated protein degradation in vitro: dependence of cytosol, calnexin and ATP. J. Cell Biol. 132, 291–298. Wang, J. and White, A. L. (2000) Role of calnexin, calreticulin, and endoplasmic reticulum mannosidase I in apolipoprotein (a) intracellular targeting. Biochemistry 39, 8993–9000. Wilson, C. M., Farmery, M. R., and Bulleid, N. J. (2000) Pivotal role of calnexin and mannose trimming in regulating the endoplasmic reticulum-associated degradation of major histocompatibility complex class I heavy chain. J. Biol. Chem. 275, 21224–21,232. Chung, D. H., Ohashi, K., Watanabe, M., Miyasaka, N., and Hirosawa, S. (2000) Mannose trimming targets mutant alpha 2 plasmin inhibitor for degradation by the proteasome. J. Biol. Chem. 275, 4981–4987. Cabral, C. M., Choudhury, P., Liu, Y., and Sifers, R. N. (2000) Processing by endoplasmic reticulum mannosidases partitions a secretion-impaired glycoprotein into distinct disposal pathways. J. Biol. Chem. 275, 25,015–25,022. Wilson, R., Allen, A. J., Oliver, J., Brookman, J. L., High, S., and Bulleid, N. J. (1995) The translocation, folding, assembly and redox-dependent degradation of secretory and membrane proteins in semi-permeabilized mammalian cells. Biochem. J. 307, 679–687. Keller, S. H., Lindstrom, J., and Taylor, P. (1998) Inhibition of glucose trimming with castanospermine reduces calnexin association and promotes proteasomal degradation of the a-subunit of the nicotinic acetylcholine receptor. J. Biol. Chem. 273, 17,064–17,072. Oda, Y., Hosokawa, N., Wada, I., and Nagata, K. (2003) EDEM as an acceptor of terminally misfolded glycoproteins released from calnexin. Science 299, 1394–1397. Molinari, M., Calanca, V., Galli, C., Lucca, P., and Pagnetti, P. (2003) Role of EDEM in the release of misfolded glycoproteins from the calnexin cycle. Science 299, 1397–1400. Nakatsukasa, K., Nishikawa, S.-I., Hosokawa, N., Nagata, K., and Endo, T. (2001) Mnl1p, an alpha-mannosidase-like protein in yeast Saccharomyces cerevisiae, is required for endoplasmic reticulum-associated degradation of glycoproteins. J. Biol. Chem. 276, 8635–8638. Jakob, C. A., Bodmer, D., Spirig, U., et al. (2001) Htm1p, a mannosidase-like protein, is involved in glycoprotein degradation in yeast. EMBO Rep. 2, 423–430. Hosokawa, N., Wada, I., Hasegawa, K., et al. (2001) A novel ER a-mannosidase-like protein accelerates ER-associated degradation. EMBO Rep. 2, 415–422. Yoshida, H., Matsui, T., Hosokawa, N., Kaufman, R. J., Nagata, K., and Mori, K. (2003) A time-dependent phase shift in the mammalian unfolded protein response. Dev. Cell 4, 265–271. Moore, S. E. H. and Spiro, R. G. (1993) Inhibition of glucose trimming by castanospermine results in rapid degradation of unsassembled major hitsocompatibility complex Class I molecules. J. Biol. Chem. 268, 3809–3812. Ayalon-Soffer, M., Shenkman, M., and Lederkremer, G. Z. (1999) Differential roles of mannose and glucose trimming in the ER degradation of asialoglycoprotein receptor subunits J. Cell Sci. 112, 3309–3318. Fagioli, C. and Sitia, R. (2001) Glycoprotein quality control in the endoplasmic reticulum. J. Biol. Chem. 276, 12,885–12,892. de Virgilio, M., Weninger, H., and Ivessa, N. E. (1998) Ubiquitin is required for the retrotranslocation of a short-lived luminal endoplasmic reticulum glycoprotein to the cytosol for degradation by the proteasome. J. Biol. Chem. 273, 9734–9743. Bebok, Z., Mazzochi, C., King, S. A., Hong, J. S., and Sorscher, E. J. (1998) The mechanism underlying cystic fibrosis transmembrane conductance regulator transport from the endoplasmic reticulum to the proteasome includes Sec61beta and a cytosolic, deglycosylated intermediary. J. Biol. Chem. 273, 29,873–29,878. Petaja-Repo, U. E., Hogue, M., Laperriere, A., Bhalla, S., Walker, P., and Bouvier, M. (2001) Newly synthesized human delta opioid receptors retained in the endoplasmic reticulum are retranslocated to the cytosol, deglycosylated, ubiquitinated, and degraded by the proteasome, J. Biol. Chem. 276, 4416–4423. Wiertz, E. J., Tortorella, D., Bogyo, M., et al. (1996) Sec61-mediated transfer of a membrane protein from the endoplasmic reticulum to the proteasome for destruction. Nature 384, 432–438. Wesche, J., Rapak, A., and Olsnes, S. (1999) Dependence of ricin toxicity on translocation of the toxin A-chain from the endoplasmic reticulum to the cytosol. J. Biol. Chem. 274, 34,443–34,449. Fisher, E. A. and Ginsberg, H. N. (2002) Complexity in the secretory pathway: the assembly and secretion of apolipoprotein B-containing lipoproteins. J. Biol. Chem. 277, 17,377–17,380. Hamman, B. D., Chen, J. C., Johnson, E. E., and Johnson, A. E. (1997) The aqueous pore through the translocon has a diameter of 40–60 Å during cotranslational protein translocation at the ER membrane. Cell 89, 535–544. Hamman, B. D., Hendershot, L. M., and Johnson, A. E. (1998) BiP maintains the permeability barrier of the ER membrane by dealing the lumenal end of the translocon before and early in translocation. Cell 92, 747–758. Kowarik, M., Kung, S., Martoglio, B., and Helenius, A. (2002) Protein folding during cotranslational translocation in the endoplasmic reticulum. Mol. Cell 10, 769–778. Tsai, B., Ye, Y., and Rapoport, T. A. (2002) Retro-translocation of proteins from the endoplasmic reticulum into the cytosol. Nature Rev. Mol. Cell. Biol. 3, 246–255. Jarosch, E., Geiss-Friedlander, R., Meusser, B., Walter, J., and Sommer, T. (2002) Protein dislocation from the endoplasmic reticulum—pulling out the suspect. Traffic 3, 530–536. Meyer, H. H., Shorter, J. G., Seemann, J., Pappin, D., and Warren, G. (2000) A complex of mammalian ufd1 and np14 links the AAA-ATPase, p97, to ubiquitin and nuclear transport pathways. EMBO J. 19, 2181–2192. Rape, M., Hoppe, T., Gorr, I., Kalocay, M., Richly, H., and Jentsch, S. (2001) Mobilization of processed, membrane-tethered SPT23 transcription factor by CDC48(UFD1/NPL4), a ubiquitin-selective chaperone. Cell 107, 667–677. Verma, R., Chen, S., Feldman, R., et al. (2000) Proteasomal proteomics: identification of nucleotide-sensitive proteasome-interacting proteins by mass spectrometric analysis of affinity-purified proteasomes. Mol. Biol. Cell 11, 3425–3439. Rabinovich, E., Kerem, A., Frohlich, K.U., Diamant, N., and Bar-Nun, S. (2002) AAA-ATPase p97/Cdc48p, a cytosolic chaperone required for endoplasmic reticulum-associated protein degradation. Mol. Cell Biol. 22, 626–634. Ye, Y., Meyer, H. H., and Rapoport, T. A. (2001) The AAA ATPase Cdc48/p97 and its partners transport proteins from the ER into the cytosol. Nature 414, 652–656. Braun, S., Matuschewski, K., Rape, M., Thomas, S., and Jentsch, S. (2002) Role of the ubiquitin-selective CDC48 (UFD1/NPL4) chaperone segregase in ERAD of OLE1 and other substrates. EMBO J. 21, 615–621. Jarosch, E., Taxis, C., Volkwein, C., et al. (2002) Protein dislocation from the ER requires polyubiquitination and the AAA-ATPase Cdc48. Nature Cell Biol. 4, 134–139. Baumeister, W., Walz, J., Zuhl, F., and Seemuller, E. (1998) The proteasome: paradigm of a self-compartmentalizing protease. Cell 92, 367–380. Voges, D., Zwickl, P., and Baumeister, W. (1999) The 26S proteasome: a molecular machine designed for controlled proteolysis. Annu. Rev. Biochem. 68, 1015–1068. Mayer, T. U., Braun, T., and Jentsch, S. (1998) Role of the proteasome in membrane extraction of a short-lived ER-membrane protein. EMBO J. 17, 3251–3257. Bays, N. W., Wilhovsky, S. K., Goradia, A., Hodgkiss-Harlow, K., and Hampton, R. Y. (2001) HRD4/NPL4 is required for the proteasomal processing of ubiquitinated ER proteins. Mol. Biol. Cell 12, 4114–4128. Qu, D. F., Teckman, J. H., Omura, S., and Perlmutter, D. H. (1996) Degradation of a mutant secretory protein, a1-antitrypsin Z, in the endoplasmic reticulum requires proteasome activity. J. Biol. Chem. 271, 22,791–22,795. Thrower, J., Hoffman, L., Rchsteiner, M., and Pickart, C. (2000) Recognition of the polyubiquitin proteolytic signal. EMBO J. 19, 94–102. Joazeiro, C. and Weissman, A. (2000) RING finger proteins: mediators of ubiquitin ligase activity. Cell 102, 549–552. Weissman, A (2001) Themes and variations on ubiquitylation. Nature Rev. Mol. Cell. Biol. 2, 169–178. Biederer, T., Volkwein, C., and Sommer, T. (1997) Role of Cuelp in ubiquitination and degradation at the ER surface. Science 278, 1806–1809. Tiwari, S. and Weissman, A. (2001) Endoplasmic reticulum (ER)-associated degradation of T cell receptor subunits. J. Biol. Chem. 276, 16,193–16,200. Fang, S., Ferrone, M., Yang, C., Jensen, J. P., Tiwari, S., and Weissman, A. M. (2001) The tumor autocrine motility factor receptor, gp78, is a ubiquitin protein ligase implicated in degradation from the endoplasmic reticulum. Proc. Natl. Acad. Sci. USA 98, 14,422–14,427. Yoshida, Y., Chiba, T., Tokunaga, F., et al. (2002) E3 ubiquitin ligase that recognizes sugar chains. Nature 418, 438–442. Suzuki, T., Park, H., and Lennarz, W. J. (2002) Cytoplasmic peptide: N-glycanase (PNGase) in eukaryotic cells: occurence, primary structure, and potential functions. FASEB J. 16, 635–641. Hirsch, C., Blom, D., and Ploegh, H. L. (2003) A role for N-glycanase in the cytosolic turnover of glycoproteins. EMBO J. 22, 1036–1046. Wiertz, E. J. H. J., Jones, T. R., Sun, L., Bogyo, M., Geuze, H. J., and Ploegh, H. L. (1996) The human cytomegalovirus US11 gene product dislocated MHC class I heavy chains from the endoplasmic reticulum to the cytosol. Cell 84, 769–779. Huppa, J. B. and Ploegh, H. L. (1997) The in vitro translation and assembly of a complete T cell receptor-CD3 complex. J. Exp. Med. 186, 393–403. Halaban, R., Chang, E., Zhang, Y., et al. (1997) Aberrant retention of tyrosinase in the endoplasmic reticulum mediates accelerated degradation of the enzyme and contributes to the dedifferentiated phenotype of amelanotic melanoma cells. Proc. Natl. Acad. Sci. USA 94, 6210–6215. Suzuki, T., Park, H., Hollingsworth, N. M., Sternglanz, R., and Lennarz, W. J. (2000) PNG1, a yeast gene encoding a highly conserved peptide: N-glycanase. J. Cell Biol. 149, 1039–1051. Suzuki, T., Park, H., Kwofie, M. A., and Lennarz, W. J. (2001) Rad23 provides a link between the Png1 deglycosylating enzyme and the 26S proteasome in yeast. J. Biol. Chem. 276, 21,601–21,607. Suzuki, T. and Lennarz, W. J. (2003) Hypothesis: a glycoprotein-degradation complex formed by protein-protein interaction involves cytoplasmic peptide: N-glycanase. Biochem. Biophys. Res. Commun. 302, 1–5. Palmer, A., Rivett, A. I., Thomson, S., et al. (1996) Subpopulations of proteasomes in rat liver nuclei, microsomes and cytosol. Biochem. J. 316, 401–407. Enenkel, C., Lehmann, A., and Kloetzel, P.-M. (1998) Subcellular distribution of proteasomes implicates a major location of protein degradation in the nuclear envelope-ER network in yeast. EMBO J. 17, 6144–6154. Hirsch, C. and Ploegh, H. L. (2000) Intracellular targeting of the proteasome. Trends Cell Biol. 10, 268–271. Chapman, R., Sidrauski, C., and Walter, P. (1998) Intracellular signaling from the endoplasmic reticulum to the nucleus. Annu. Rev. Cell Dev. Biol. 14, 459–485. Travers, K. J., Patil, C. K., Wodicka, L., Lockhart, D. J., Weissman, J. S., and Walter, P. (2000) Functional and genomic analyses reveal an essential coordination between unfolded protein response and ER-associated degradation. Cell 101, 249–258. Harding, H. P., Calfon, M., Urano, F., and Ron, D. (2002) Transcriptional and translational control in mammalian unfolded protein response. Annu. Rev. Cell Dev. Biol. 18, 575–599. Harding, H. P., Zhang, Y., and Ron, D. (1999) Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase. Nature 397, 271–274. Kaufman, R. J. (1999) Stress signaling from the lumen of the endoplasmic reticulum: coordination of gene transcriptional and translational controls. Genes Dev. 13, 1211–1233. Yoshida, H., Haze, K., Yanagi, H., Yura, T., and Mori, K. (1998) Identification of the cis-acting endoplasmic reticulum stress response element responsible for transcriptional induction of mammalian glucose-regulated proteins. J. Biol. Chem. 273, 33,741–33,749. Brown, M. S., Ye, J., Rawson, R. B., and Goldstein, J. L. (2000) Regulated intramembrane proteolysis: a control mechanism conserved from bacteria to humans. Cell 100, 391–398. Ye, J., Rawson, R. B., Komuru, R., et al. (2000) ER stress induces cleavage of membrane-bound ATF6 by the same proteases that process SREBPs. Mol. Cell 6, 1355–1364. Shen, X., Ellis, R. E., Lee, K., et al. (2001) Complementary signaling pathways regulate the unfolded protein response and are required for C. elegans development. Cell 107, 893–903. Yoshida, H., Matsui, T., Yamamoto, A., Okada, T., and Mori, K. (2001) XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor. Cell 107, 881–891. Casagrande, R., Stern, P., Diehn, M., et al. (2000) Degradation of proteins from the ER of S. cerevisiae requires an intact unfolded protein response pathway. Mol. Cell 5, 729–735. Ng, D. T. W., Spear, E. D., and Walter, P. (2000) The unfolded protein response regulates multiple aspects of secretory and membrane protein biogenesis and endoplasmic reticulum quality control. J. Cell Biol. 150, 77–88. Friedlander, R., Jarosch, E., Urban, J., Volkwein, C., and Sommer, T. (2000) A regulatory link between ER-associated protein degradation and the unfolded-protein response. NatNature Cell Biol. 2, 379–384.