Role of N -linked polymannose oligosaccharides in targeting glycoproteins for endoplasmic reticulum-associated degradation

Abstract

Misfolded or incompletely assembled multisubunit glycoproteins undergo endoplasmic reticulum-associated degradation (ERAD) regulated in large measure by their N-linked polymannose oligosaccharides. In this quality control system lectin interaction with Glc(3)Man(9)GlcNAc(2) glycans after trimming with endoplasmic reticulum (ER) alpha-glucosidases and alpha-mannosidases sorts out persistently unfolded glycoproteins for N-deglycosylation and proteolytic degradation. Monoglucosylated (Glc(1)Man(9)GlcNAc(2)) glycoproteins take part in the calnexin/calreticulin glucosylation-deglucosylation cycle, while the Man(8)GlcNAc(2) isomer B product of ER mannosidase I interacts with EDEM. Proteasomal degradation requires retrotranslocation into the cytosol through a Sec61 channel and deglycosylation by peptide: N-glycosidase (PNGase); in alternate models both PNGase and proteasomes may be either free in the cytosol or ER membrane-imbedded/attached. Numerous proteins appear to undergo nonproteasomal degradation in which deglycosylation and proteolysis take place in the ER lumen. The released free oligosaccharides (OS) are transported to the cytosol as OS-GlcNAc(2) along with similar components produced by the hydrolytic action of the oligosaccharyltransferase, where they together with OS from the proteasomal pathway are trimmed to Man(5)GlcNAc(1) by the action of cytosolic endo-beta- N-acetylglucosaminidase and alpha-mannosidase before entering the lysosomes. Some misfolded glycoproteins can recycle between the ER, intermediate and Golgi compartments, where they are further processed before ERAD. Moreover, properly folded glycoproteins with mannose-trimmed glycans can be deglucosylated in the Golgi by endomannosidase, thereby releasing calreticulin and permitting formation of complex OS. A number of regulatory controls have been described, including the glucosidase-glucosyltransferase shuttle, which controls the level of Glc(3)Man(9)GlcNAc(2)-P-P-Dol, and the unfolded protein response, which enhances synthesis of components of the quality control system.

Changes in Structural Features of FreeN-Glycan and Endoglycosidase Activity during Tomato Fruit Ripening

“…[22][23][24] In previous studies, 25,26) however, we purified an -mannosidase from Ginkgo seeds that was activated by cobalt ion and preferred highmannose type glycans with one GlcNAc residue rather than those with the chitobiosyl unit. Since these enzymatic properties are very similar to those of animal cytosolic -mannosidase [22][23][24] that has been thought to be involved in the degradation of high-mannose type free N-glycans produced by PNGase and ENGase in animal cells, [19][20][21][22] Ginkgo -mannosidase might be responsible for the degradation of high-mannose type free N-glycans in the cytosol. Furthermore, this speculation is supported by another fact that the Ginkgo enzyme converted Man 9 GlcNAcNAc 1 to a Man 5 GlcNAc 1 isomer, Man 1-6(Man 1-3)Man 1-6(Man 1-3)Man 1-4GlcNAc, found specifically in plant cells but not to the Man 1-6(Man 1-2Man 1-2Man 1-3)Man 1-4GlcNAc structure found in animal cells.…”

“…It is reasonable to assume, therefore, that the endogenous substrates for plant ENGase must be misfolded glycoproteins translocated from ER as well as substrates for animal ENGase. [18][19][20][21] We recently identified and succeeded in expressing endo--N-acetylglucosaminidase genes of rice (endo-OS) and tomato (endo-LE), and found that the plant ENGases are expressed in growing tissues of the hypocotyls of rice seedlings. [28][29][30] Suppression and enhancement of ENGase activity by gene manipulation in plant cells should provide detailed information on the physiological roles of ENGase and the resulting highmannose type free N-glycans.…”

“…7-II), but such small differences in specific activity do not account for the enormous differences in the amounts of free N-glycans. These results suggest that ENGase activity is maintained at a certain level through the fruit ripening process to eliminate misfolded nascent glycoproteins, as animal ENGases play a critical role in the ER-associated degradation system (ERAD), [19][20][21] although the turnover or degradation rate of the resulting high-mannose type free N-glycans might vary with fruit ripening and thus cause significant differences in the amounts accumulated.…”

The Retrotranslocation Protein Derlin-1 Binds Peptide:N-Glycanase to the Endoplasmic Reticulum

“…In this quality control system, lectin-like molecular chaperones, calnexin and calreticulin, recognize the Glc 1 Man 9 GlcNAc 2 oligosaccharide and assist in folding of newly synthesized glycoproteins. Lectin interaction with Glc 1 Man 9 GlcNAc 2 glycans after trimming with ER alpha-glucosidases, and alpha-mannosidases sorts out persistently unfolded glycoproteins for N-deglycosylation and degradation by the proteasome (Cresswell and Hughes, 1997;Kopito, 1997;Brodsky and McCracken, 1999;Romisch, 1999;Spiro, 2004).The mannose trimming of N-linked glycans plays an important role in the ERAD of glycoproteins (Spiro, 2004). In both yeast and human cells, it is reported that the misfolded glycoproteins in the ER are degraded through ERAD only after the glycan is trimmed to the Man8B form, while misfolded proteins stay within the ER when they retain the Man9 form of oligosaccharides.…”

“…The misfolded glycoproteins exit the ER via a multiprotein complex referred to as a retrotranslocon or dislocon (Plemper et al, 1997;Bebok et al, 1998;de Virgilio et al, 1998;Tsai et al, 2002). In alternative models both PNGase and proteasomes may be either free in the cytosol or ER membrane imbedded or attached (Spiro, 2004).A well-studied model for the ERAD pathway utilizes the human cytomegalovirus, which affects the MHC class I antigen presentation. The virally encoded proteins US2 and US11 act on the misfolded MHC class I heavy chains (HC) and catalyze their exit from ER to the cytosol.…”