ER-resident protein 46 (ERp46) triggers the mannose-trimming activity of ER degradation–enhancing α-mannosidase–like protein 3 (EDEM3)

Yu, Shangyu; Ito, S; Wada, Ikuo; Hosokawa, Nobuko

doi:10.1074/jbc.ra118.003129

Cited by 33 publications

(32 citation statements)

References 43 publications

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“…TXNDC11 was recently reported to be a disulfide reductase with a role in ERAD and to associate with EDEM2 and EDEM3 27 . Very recently, while this manuscript was in revision, it was reported that EDEM3 associates with another oxidoreductase, ERp46, which promotes its mannose-trimming activity 18 . In this case, the redox environment did not affect EDEM3 activity, and thus ERp46 did not affect EDEM3 per se, suggesting that the complex may reduce the misfolded substrate.…”

Section: Discussionmentioning

confidence: 95%

“…Although it was shown that overexpression or depletion of the EDEMs affects the trimming of mannose residues (EDEM1 11 , 15 , 16 , EDEM2 12 , EDEM3 17 ), mannosidase activity has not yet been established in vitro for EDEM1 and EDEM2. Mannosidase activity has already been determined in vitro for ERManI and mannosidase IA and very recently for EDEM3 18 . It has also been reported for the Saccharomyces cerevisiae EDEM homolog Htm1, which functions in a complex with protein disulfide isomerase (PDI) 19 – 22 .…”

Section: Introductionmentioning

confidence: 99%

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Mannosidase activity of EDEM1 and EDEM2 depends on an unfolded state of their glycoprotein substrates

et al. 2018

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Extensive mannose trimming of nascent glycoprotein N-glycans signals their targeting to endoplasmic reticulum-associated degradation (ERAD). ER mannosidase I (ERManI) and the EDEM protein family participate in this process. However, whether the EDEMs are truly mannosidases can be addressed only by measuring mannosidase activity in vitro. Here, we reveal EDEM1 and EDEM2 mannosidase activities in vitro. Whereas ERManI significantly trims free N-glycans, activity of the EDEMs is modest on free oligosaccharides and on glycoproteins. However, mannosidase activity of ERManI and the EDEMs is significantly higher on a denatured glycoprotein. The EDEMs associate with oxidoreductases, protein disulfide isomerase, and especially TXNDC11, enhancing mannosidase activity on glycoproteins but not on free N-glycans. The finding that substrate unfolded status increases mannosidase activity solves an important conundrum, as current models suggest general slow mannose trimming. As we show, misfolded or unfolded glycoproteins are subject to differentially faster trimming (and targeting to ERAD) than well-folded ones.

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Section: Discussionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

Mannosidase activity of EDEM1 and EDEM2 depends on an unfolded state of their glycoprotein substrates

et al. 2018

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“…Likewise, ERdj3 was recently implicated in the degradation of the Z variant (37). Additionally, the EDEM3 MLD was recently discovered to form a disulfide bond with the oxidoreductase ERp46, which promoted the catalytic activity of EDEM3 (38). Whether these oxidoreductases or others are involved in the redox-sensitive substrate-binding properties of EDEM1 remains to be determined.…”

Section: Edem1 Redox-sensitive Binding and Catalytic Activitymentioning

confidence: 99%

EDEM1's mannosidase-like domain binds ERAD client proteins in a redox-sensitive manner and possesses catalytic activity

Lamriben

Oster

Tamura

et al. 2018

Journal of Biological Chemistry

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Endoplasmic reticulum (ER) degradation-enhancing α-mannosidase-like 1 protein (EDEM1) is a protein quality control factor that was initially proposed to recognize -linked glycans on misfolded proteins through its mannosidase-like domain (MLD). However, recent studies have demonstrated that EDEM1 binds to some misfolded proteins in a glycan-independent manner, suggesting a more complex binding landscape for EDEM1. In this study, we have identified a thiol-dependent substrate interaction between EDEM1 and the α-antitrypsin ER-associated protein degradation (ERAD) clients Z and NHK, specifically through the single Cys residue on Z/NHK (Cys), required for binding under stringent detergent conditions. In addition to the thiol-dependent interaction, the presence of weaker protein-protein interactions was confirmed, suggestive of bipartite client-binding properties. About four reactive thiols on EDEM1 were identified and were not directly responsible for the observed redox-sensitive binding by EDEM1. Moreover, a protein construct comprising the EDEM1 MLD had thiol-dependent binding properties along with its active glycan-trimming activities. Lastly, we identified an additional intrinsically disordered region (IDR) located at the C terminus of EDEM1 in addition to its previously identified N-terminal IDR. We also determined that both IDRs are required for binding to the ERAD component ERdj5 as an interaction with ERdj5 was not observed with the MLD alone. Together, our findings indicate that EDEM1 employs different binding modalities to interact with ERAD clients and ER quality control (ERQC) machinery partners and that some of these properties are shared with its homologues EDEM2 and EDEM3.

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“…A recent study revealed that EDEM3 can associate stably with ERp46 (also called TXNDC5), another ER-resident oxidoreductase. This association was required for the mannosidase activity on misfolded substrate glycoproteins [ 67 ]. In vitro degradation of misfolded TCRα was reconstituted only when ERp46 had established a covalent interaction with EDEM3.…”

Section: Involvement Of Oxidoreductases In Mannose Trimming Of Unfmentioning

confidence: 99%

“…This interaction, which depended on the redox activity of ERp46, involved formation of a disulfide bond between the cysteine residues of the ERp46 catalytic sites and the EDEM3 α-mannosidase domain. ERp46 does not directly change EDEM3 activity, and probably plays a role similar to that of TXNDC11 and PDI for EDEM1 and 2 activity, acting on the glycoprotein substrate [ 67 ]. Another study found a thiol-dependent substrate association of EDEM1 with the misfolded α1-antitrypsin variant Null Hong Kong (NHK), through a single Cys residue of the substrate, but this did not involve EDEM1 thiols.…”

Section: Involvement Of Oxidoreductases In Mannose Trimming Of Unfmentioning

confidence: 99%

Oxidoreductases in Glycoprotein Glycosylation, Folding, and ERAD

Patel

Saad

Shenkman

et al. 2020

Cells

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N-linked glycosylation and sugar chain processing, as well as disulfide bond formation, are among the most common post-translational protein modifications taking place in the endoplasmic reticulum (ER). They are essential modifications that are required for membrane and secretory proteins to achieve their correct folding and native structure. Several oxidoreductases responsible for disulfide bond formation, isomerization, and reduction have been shown to form stable, functional complexes with enzymes and chaperones that are involved in the initial addition of an N-glycan and in folding and quality control of the glycoproteins. Some of these oxidoreductases are selenoproteins. Recent studies also implicate glycan machinery–oxidoreductase complexes in the recognition and processing of misfolded glycoproteins and their reduction and targeting to ER-associated degradation. This review focuses on the intriguing cooperation between the glycoprotein-specific cell machineries and ER oxidoreductases, and highlights open questions regarding the functions of many members of this large family.

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ER-resident protein 46 (ERp46) triggers the mannose-trimming activity of ER degradation–enhancing α-mannosidase–like protein 3 (EDEM3)

Cited by 33 publications

References 43 publications

Mannosidase activity of EDEM1 and EDEM2 depends on an unfolded state of their glycoprotein substrates

Mannosidase activity of EDEM1 and EDEM2 depends on an unfolded state of their glycoprotein substrates

EDEM1's mannosidase-like domain binds ERAD client proteins in a redox-sensitive manner and possesses catalytic activity

Oxidoreductases in Glycoprotein Glycosylation, Folding, and ERAD

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