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EDEM2 initiates mammalian glycoprotein ERAD by catalyzing the first mannose trimming step

Glycoproteins misfolded in the endoplasmic reticulum (ER) are subjected to ER-associated glycoprotein degradation (gpERAD) in which Htm1-mediated mannose trimming from the oligosaccharide Man(8)GlcNAc(2) to Man(7)GlcNAc(2) is the rate-limiting step in yeast. In contrast, the roles of the three Htm1...

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Autores principales: Ninagawa, Satoshi, Okada, Tetsuya, Sumitomo, Yoshiki, Kamiya, Yukiko, Kato, Koichi, Horimoto, Satoshi, Ishikawa, Tokiro, Takeda, Shunichi, Sakuma, Tetsushi, Yamamoto, Takashi, Mori, Kazutoshi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4121980/
https://www.ncbi.nlm.nih.gov/pubmed/25092655
http://dx.doi.org/10.1083/jcb.201404075
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author Ninagawa, Satoshi
Okada, Tetsuya
Sumitomo, Yoshiki
Kamiya, Yukiko
Kato, Koichi
Horimoto, Satoshi
Ishikawa, Tokiro
Takeda, Shunichi
Sakuma, Tetsushi
Yamamoto, Takashi
Mori, Kazutoshi
author_facet Ninagawa, Satoshi
Okada, Tetsuya
Sumitomo, Yoshiki
Kamiya, Yukiko
Kato, Koichi
Horimoto, Satoshi
Ishikawa, Tokiro
Takeda, Shunichi
Sakuma, Tetsushi
Yamamoto, Takashi
Mori, Kazutoshi
author_sort Ninagawa, Satoshi
collection PubMed
description Glycoproteins misfolded in the endoplasmic reticulum (ER) are subjected to ER-associated glycoprotein degradation (gpERAD) in which Htm1-mediated mannose trimming from the oligosaccharide Man(8)GlcNAc(2) to Man(7)GlcNAc(2) is the rate-limiting step in yeast. In contrast, the roles of the three Htm1 homologues (EDEM1/2/3) in mammalian gpERAD have remained elusive, with a key controversy being whether EDEMs function as mannosidases or as lectins. We therefore conducted transcription activator-like effector nuclease–mediated gene knockout analysis in human cell line and found that all endogenous EDEMs possess mannosidase activity. Mannose trimming from Man(8)GlcNAc(2) to Man(7)GlcNAc(2) is performed mainly by EDEM3 and to a lesser extent by EDEM1. Most surprisingly, the upstream mannose trimming from Man(9)GlcNAc(2) to Man(8)GlcNAc(2) is conducted mainly by EDEM2, which was previously considered to lack enzymatic activity. Based on the presence of two rate-limiting steps in mammalian gpERAD, we propose that mammalian cells double check gpERAD substrates before destruction by evolving EDEM2, a novel-type Htm1 homologue that catalyzes the first mannose trimming step from Man(9)GlcNAc(2).
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spelling pubmed-41219802015-02-04 EDEM2 initiates mammalian glycoprotein ERAD by catalyzing the first mannose trimming step Ninagawa, Satoshi Okada, Tetsuya Sumitomo, Yoshiki Kamiya, Yukiko Kato, Koichi Horimoto, Satoshi Ishikawa, Tokiro Takeda, Shunichi Sakuma, Tetsushi Yamamoto, Takashi Mori, Kazutoshi J Cell Biol Research Articles Glycoproteins misfolded in the endoplasmic reticulum (ER) are subjected to ER-associated glycoprotein degradation (gpERAD) in which Htm1-mediated mannose trimming from the oligosaccharide Man(8)GlcNAc(2) to Man(7)GlcNAc(2) is the rate-limiting step in yeast. In contrast, the roles of the three Htm1 homologues (EDEM1/2/3) in mammalian gpERAD have remained elusive, with a key controversy being whether EDEMs function as mannosidases or as lectins. We therefore conducted transcription activator-like effector nuclease–mediated gene knockout analysis in human cell line and found that all endogenous EDEMs possess mannosidase activity. Mannose trimming from Man(8)GlcNAc(2) to Man(7)GlcNAc(2) is performed mainly by EDEM3 and to a lesser extent by EDEM1. Most surprisingly, the upstream mannose trimming from Man(9)GlcNAc(2) to Man(8)GlcNAc(2) is conducted mainly by EDEM2, which was previously considered to lack enzymatic activity. Based on the presence of two rate-limiting steps in mammalian gpERAD, we propose that mammalian cells double check gpERAD substrates before destruction by evolving EDEM2, a novel-type Htm1 homologue that catalyzes the first mannose trimming step from Man(9)GlcNAc(2). The Rockefeller University Press 2014-08-04 /pmc/articles/PMC4121980/ /pubmed/25092655 http://dx.doi.org/10.1083/jcb.201404075 Text en © 2014 Ninagawa et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).
spellingShingle Research Articles
Ninagawa, Satoshi
Okada, Tetsuya
Sumitomo, Yoshiki
Kamiya, Yukiko
Kato, Koichi
Horimoto, Satoshi
Ishikawa, Tokiro
Takeda, Shunichi
Sakuma, Tetsushi
Yamamoto, Takashi
Mori, Kazutoshi
EDEM2 initiates mammalian glycoprotein ERAD by catalyzing the first mannose trimming step
title EDEM2 initiates mammalian glycoprotein ERAD by catalyzing the first mannose trimming step
title_full EDEM2 initiates mammalian glycoprotein ERAD by catalyzing the first mannose trimming step
title_fullStr EDEM2 initiates mammalian glycoprotein ERAD by catalyzing the first mannose trimming step
title_full_unstemmed EDEM2 initiates mammalian glycoprotein ERAD by catalyzing the first mannose trimming step
title_short EDEM2 initiates mammalian glycoprotein ERAD by catalyzing the first mannose trimming step
title_sort edem2 initiates mammalian glycoprotein erad by catalyzing the first mannose trimming step
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4121980/
https://www.ncbi.nlm.nih.gov/pubmed/25092655
http://dx.doi.org/10.1083/jcb.201404075
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