STT3B-Dependent Posttranslational N-Glycosylation as a Surveillance System for Secretory Protein

Satō, Takashi; Sako, Yasuhiro; Sho, Misato; Momohara, Mamiko; Suico, Mary Ann; Shuto, Tsuyoshi; Nishitoh, Hideki; Okiyoneda, Tsukasa; Kokame, Koichi; Kaneko, Masayuki; Taura, Manabu; Miyata, Masanori; Chosa, Keisuke; Koga, Tomoaki; Morino-Koga, Saori; Wada, Ikuo; Kai, Hirofumi

doi:10.1016/j.molcel.2012.04.015

Cited by 68 publications

(66 citation statements)

References 42 publications

(62 reference statements)

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“…D18G TTR is an amyloidogenic disease-associated mutant that is inefficiently secreted and subject to ERAD (Hammarstrom, et al, 2003; Sekijima, et al, 2005). This variant has been shown to be post-translationally glycosylated by OST to prevent aggregation and to facilitate degradation (Sato, et al, 2012). …”

Section: Resultsmentioning

confidence: 99%

Enhanced Aromatic Sequons Increase Oligosaccharyltransferase Glycosylation Efficiency and Glycan Homogeneity

Murray

Chen

Antonopoulos

et al. 2015

Chemistry & Biology

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SUMMARY N-glycosylation plays an important role in protein folding and function. Previous studies demonstrate that a phenylalanine residue introduced at the n-2 position relative to an Asn-Xxx-Thr/Ser N-glycosylation sequon increases the sequon’s glycan occupancy in insect cells. Here, we show that any aromatic residue at n-2 increases glycan occupancy in human cells, and we show that this effect is dependent upon oligosaccharyltransferase substrate preferences rather than differences in other cellular processing events such as degradation or trafficking. Moreover, aromatic residues at n-2 alter glycan processing in the Golgi, producing proteins with less complex N-glycan structures. These results demonstrate that manipulating the sequence space surrounding N-glycosylation sequons is useful both for controlling glycosylation efficiency, thus enhancing glycan occupancy, and for influencing the N-glycan structures produced.

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Section: Resultsmentioning

confidence: 99%

Enhanced Aromatic Sequons Increase Oligosaccharyltransferase Glycosylation Efficiency and Glycan Homogeneity

Murray

Chen

Antonopoulos

et al. 2015

Chemistry & Biology

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“…A recent study implicated EDEM3 in the degradation of glycosylated TTR mutant proteins [39]. But even though mannosidase activity for EDEM3 been shown in vivo [36], it is still not clear whether mannose processing by EDEM3 was essential for degradation of the mutant proteins [39].…”

Section: Discussionmentioning

confidence: 99%

“…But even though mannosidase activity for EDEM3 been shown in vivo [36], it is still not clear whether mannose processing by EDEM3 was essential for degradation of the mutant proteins [39]. And even though EDEM3 contributed to the degradation of glycosylated SHH-C, it may not be utilizing the SHH-C glycan for its recognition and degradation.…”

Section: Discussionmentioning

confidence: 99%

EDEM2 and OS-9 Are Required for ER-Associated Degradation of Non-Glycosylated Sonic Hedgehog

et al. 2014

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Misfolded proteins of the endoplasmic reticulum (ER) are eliminated by the ER-associated degradation (ERAD) in eukaryotes. In S. cerevisiae, ER-resident lectins mediate substrate recognition through bipartite signals consisting of an unfolded local structure and the adjacent glycan. Trimming of the glycan is essential for the directional delivery of the substrates. Whether a similar recognition and delivery mechanism exists in mammalian cells is unknown. In this study, we systematically study the function and substrate specificity of known mammalian ER lectins, including EDEM1/2/3, OS-9 and XTP-3B using the recently identified ERAD substrate sonic hedgehog (SHH), a soluble protein carrying a single N-glycan, as well as its nonglycosylated mutant N278A. Efficient ERAD of N278A requires the core processing complex of HRD1, SEL1L and p97, similar to the glycosylated SHH. While EDEM2 was required for ERAD of both glycosylated and non-glycosylated SHHs, EDEM3 was only necessary for glycosylated SHH and EDEM1 was dispensable for both. Degradation of SHH and N278A also required OS-9, but not the related lectin XTP3-B. Robust interaction of both EDEM2 and OS-9 with a non-glycosylated SHH variant indicates that the misfolded polypeptide backbone, rather than a glycan signature, functions as the predominant signal for recognition for ERAD. Notably, SHH-N278A is the first nonglycosylated substrate to require EDEM2 for recognition and targeting for ERAD. EDEM2 also interacts with calnexin and SEL1L, suggesting a potential avenue by which misfolded glycoproteins may be shunted towards SEL1L and ERAD rather than being released into the secretory pathway. Thus, ER lectins participate in the recognition and delivery of misfolded ER substrates differently in mammals, with an underlying mechanism distinct from that of S. cerevisiae.

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“…Interestingly, glycosylated proteins utilize glycosylation-independent ERAD pathways during ER stress conditions (183) or if the substrate is severely misfolded (126), indicating that the substrate folding state can function as the dominant degradation signal. In rare cases, substrate misfolding exposes a cryptic glycosylation site that enables posttranslational glycosylation by STT3B-containing oligosaccharyltransferase complexes and the engagement of glycan-dependent ERAD mechanisms (148). …”

Section: Erad Mechanismmentioning

confidence: 99%

Endoplasmic Reticulum–Associated Degradation and Lipid Homeostasis

2016

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The endoplasmic reticulum is the port of entry for proteins into the secretory pathway and the site of synthesis for several important lipids, including cholesterol, triacylglycerol, and phospholipids. Protein production within the endoplasmic reticulum is tightly regulated by a cohort of resident machinery that coordinates the folding, modification, and deployment of secreted and integral membrane proteins. Proteins failing to attain their native conformation are degraded through the endoplasmic reticulum–associated degradation (ERAD) pathway via a series of tightly coupled steps: substrate recognition, dislocation, and ubiquitin-dependent proteasomal destruction. The same ERAD machinery also controls the flux through various metabolic pathways by coupling the turnover of metabolic enzymes to the levels of key metabolites. We review the current understanding and biological significance of ERAD-mediated regulation of lipid metabolism in mammalian cells.

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STT3B-Dependent Posttranslational N-Glycosylation as a Surveillance System for Secretory Protein

Cited by 68 publications

References 42 publications

Enhanced Aromatic Sequons Increase Oligosaccharyltransferase Glycosylation Efficiency and Glycan Homogeneity

Enhanced Aromatic Sequons Increase Oligosaccharyltransferase Glycosylation Efficiency and Glycan Homogeneity

EDEM2 and OS-9 Are Required for ER-Associated Degradation of Non-Glycosylated Sonic Hedgehog

Endoplasmic Reticulum–Associated Degradation and Lipid Homeostasis

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