UGGT1-mediated reglucosylation of N-glycan competes with ER-associated degradation of unstable and misfolded glycoproteins

How the fate (folding versus degradation) of glycoproteins is determined in the endoplasmic reticulum (ER) is an intriguing question. Monoglucosylated glycoproteins are recognized by lectin chaperones to facilitate their folding, whereas glycoproteins exposing well-trimmed mannoses are subjected to glycoprotein ER-associated degradation (gpERAD); we have elucidated how mannoses are sequentially trimmed by EDEM family members (George et al., 2020; 2021 eLife). Although reglucosylation by UGGT was previously reported to have no effect on substrate degradation, here we directly tested this notion using cells with genetically disrupted UGGT1/2. Strikingly, the results showed that UGGT1 delayed the degradation of misfolded substrates and unstable glycoproteins including ATF6α. An experiment with a point mutant of UGGT1 indicated that the glucosylation activity of UGGT1 was required for the inhibition of early glycoprotein degradation. These and overexpression-based competition experiments suggested that the fate of glycoproteins is determined by a tug-of-war between structure formation by UGGT1 and degradation by EDEMs. We further demonstrated the physiological importance of UGGT1, since ATF6α cannot function properly without UGGT1. Thus, our work strongly suggests that UGGT1 is a central factor in ER protein quality control via the regulation of both glycoprotein folding and degradation.

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Journal
eLife
Published
2024-12-10
DOI
https://doi.org/10.7554/elife.93117.4
Citations
2
Primary Topic
Glycosylation and Glycoproteins Research
Type
article
Field-Weighted Citation Impact
0.47

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article

UGGT1-mediated reglucosylation of N-glycan competes with ER-associated degradation of unstable and misfolded glycoproteins

Satoshi Ninagawa, Kazutoshi Matsushita, Shunsuke Saito, Deng Ying et al.
2 citations
eLife
Glycosylation and Glycoproteins Research
0.47
article

UGGT1-mediated reglucosylation of N-glycan competes with ER-associated degradation of unstable and misfolded glycoproteins

Satoshi Ninagawa, Kazutoshi Matsushita, Shunsuke Saito, Deng Ying, Kazutoshi Mori, Tetsushi Sakuma, Kaoru Sugasawa, Koshi Imami, Koichi Kato, Takashi Yamamoto, Hirokazu Yagi, Yasuhiko Kizuka, Akane Fueki, Mai Taniguchi, Shuichiro Oshita, Masaki Matsuo, Shinya Aso, Moe Yamashiro
article en
2 citations

Abstract

How the fate (folding versus degradation) of glycoproteins is determined in the endoplasmic reticulum (ER) is an intriguing question. Monoglucosylated glycoproteins are recognized by lectin chaperones to facilitate their folding, whereas glycoproteins exposing well-trimmed mannoses are subjected to glycoprotein ER-associated degradation (gpERAD); we have elucidated how mannoses are sequentially trimmed by EDEM family members (George et al., 2020; 2021 eLife). Although reglucosylation by UGGT was previously reported to have no effect on substrate degradation, here we directly tested this notion using cells with genetically disrupted UGGT1/2. Strikingly, the results showed that UGGT1 delayed the degradation of misfolded substrates and unstable glycoproteins including ATF6α. An experiment with a point mutant of UGGT1 indicated that the glucosylation activity of UGGT1 was required for the inhibition of early glycoprotein degradation. These and overexpression-based competition experiments suggested that the fate of glycoproteins is determined by a tug-of-war between structure formation by UGGT1 and degradation by EDEMs. We further demonstrated the physiological importance of UGGT1, since ATF6α cannot function properly without UGGT1. Thus, our work strongly suggests that UGGT1 is a central factor in ER protein quality control via the regulation of both glycoprotein folding and degradation.

eLifeVol. 12
Hiroshima University (JP), Scripps Research Institute (US), National Institutes of Natural Sciences (JP), Kyoto University (JP), Nagoya City University (JP), Institute for Molecular Science (JP), RIKEN Center for Integrative Medical Sciences (JP), Living Systems (United States) (US), Gifu University (JP), Kobe University (JP)
Naito Foundation, Ministry of Education, Culture, Sports, Science and Technology, Takeda Medical Research Foundation, Nagase Science Technology Foundation, Biosignal Research Center, Kobe University, Japan Society for the Promotion of Science, Japan Science and Technology Agency, Core Research for Evolutional Science and Technology
Openalex Percentile: Top 34%
Glycosylation and Glycoproteins Research
0.47
DOIOpen Access PDFOpenAlex
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