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Shedding of N-acetylglucosaminyltransferase-V is regulated by maturity of cellular N-glycan

The number of N-glycan branches on glycoproteins is closely related to the development and aggravation of various diseases. Dysregulated formation of the branch produced by N-acetylglucosaminyltransferase-V (GnT-V, also called as MGAT5) promotes cancer growth and malignancy. However, it is largely u...

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Autores principales: Hirata, Tetsuya, Takata, Misaki, Tokoro, Yuko, Nakano, Miyako, Kizuka, Yasuhiko
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9343384/
https://www.ncbi.nlm.nih.gov/pubmed/35915223
http://dx.doi.org/10.1038/s42003-022-03697-y
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author Hirata, Tetsuya
Takata, Misaki
Tokoro, Yuko
Nakano, Miyako
Kizuka, Yasuhiko
author_facet Hirata, Tetsuya
Takata, Misaki
Tokoro, Yuko
Nakano, Miyako
Kizuka, Yasuhiko
author_sort Hirata, Tetsuya
collection PubMed
description The number of N-glycan branches on glycoproteins is closely related to the development and aggravation of various diseases. Dysregulated formation of the branch produced by N-acetylglucosaminyltransferase-V (GnT-V, also called as MGAT5) promotes cancer growth and malignancy. However, it is largely unknown how the activity of GnT-V in cells is regulated. Here, we discover that the activity of GnT-V in cells is selectively upregulated by changing cellular N-glycans from mature to immature forms. Our glycomic analysis further shows that loss of terminal modifications of N-glycans resulted in an increase in the amount of the GnT-V-produced branch. Mechanistically, shedding (cleavage and extracellular secretion) of GnT-V mediated by signal peptide peptidase-like 3 (SPPL3) protease is greatly inhibited by blocking maturation of cellular N-glycans, resulting in an increased level of GnT-V protein in cells. Alteration of cellular N-glycans hardly impairs expression or localization of SPPL3; instead, SPPL3-mediated shedding of GnT-V is shown to be regulated by N-glycans on GnT-V, suggesting that the level of GnT-V cleavage is regulated by its own N-glycan structures. These findings shed light on a mechanism of secretion-based regulation of GnT-V activity.
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spelling pubmed-93433842022-08-03 Shedding of N-acetylglucosaminyltransferase-V is regulated by maturity of cellular N-glycan Hirata, Tetsuya Takata, Misaki Tokoro, Yuko Nakano, Miyako Kizuka, Yasuhiko Commun Biol Article The number of N-glycan branches on glycoproteins is closely related to the development and aggravation of various diseases. Dysregulated formation of the branch produced by N-acetylglucosaminyltransferase-V (GnT-V, also called as MGAT5) promotes cancer growth and malignancy. However, it is largely unknown how the activity of GnT-V in cells is regulated. Here, we discover that the activity of GnT-V in cells is selectively upregulated by changing cellular N-glycans from mature to immature forms. Our glycomic analysis further shows that loss of terminal modifications of N-glycans resulted in an increase in the amount of the GnT-V-produced branch. Mechanistically, shedding (cleavage and extracellular secretion) of GnT-V mediated by signal peptide peptidase-like 3 (SPPL3) protease is greatly inhibited by blocking maturation of cellular N-glycans, resulting in an increased level of GnT-V protein in cells. Alteration of cellular N-glycans hardly impairs expression or localization of SPPL3; instead, SPPL3-mediated shedding of GnT-V is shown to be regulated by N-glycans on GnT-V, suggesting that the level of GnT-V cleavage is regulated by its own N-glycan structures. These findings shed light on a mechanism of secretion-based regulation of GnT-V activity. Nature Publishing Group UK 2022-08-01 /pmc/articles/PMC9343384/ /pubmed/35915223 http://dx.doi.org/10.1038/s42003-022-03697-y Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Hirata, Tetsuya
Takata, Misaki
Tokoro, Yuko
Nakano, Miyako
Kizuka, Yasuhiko
Shedding of N-acetylglucosaminyltransferase-V is regulated by maturity of cellular N-glycan
title Shedding of N-acetylglucosaminyltransferase-V is regulated by maturity of cellular N-glycan
title_full Shedding of N-acetylglucosaminyltransferase-V is regulated by maturity of cellular N-glycan
title_fullStr Shedding of N-acetylglucosaminyltransferase-V is regulated by maturity of cellular N-glycan
title_full_unstemmed Shedding of N-acetylglucosaminyltransferase-V is regulated by maturity of cellular N-glycan
title_short Shedding of N-acetylglucosaminyltransferase-V is regulated by maturity of cellular N-glycan
title_sort shedding of n-acetylglucosaminyltransferase-v is regulated by maturity of cellular n-glycan
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9343384/
https://www.ncbi.nlm.nih.gov/pubmed/35915223
http://dx.doi.org/10.1038/s42003-022-03697-y
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