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Redefining GBA gene structure unveils the ability of Cap-independent, IRES-dependent gene regulation

Glucosylceramide is the primary molecule of glycosphingolipids, and its metabolic regulation is crucial for life. Defects in the catabolizing enzyme, glucocerebrosidase (GCase), cause a lysosomal storage disorder known as Gaucher disease. However, the genetic regulation of GCase has not been fully u...

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Autores principales: Miyoshi, Keiko, Hagita, Hiroko, Horiguchi, Taigo, Tanimura, Ayako, Noma, Takafumi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9279297/
https://www.ncbi.nlm.nih.gov/pubmed/35831491
http://dx.doi.org/10.1038/s42003-022-03577-5
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author Miyoshi, Keiko
Hagita, Hiroko
Horiguchi, Taigo
Tanimura, Ayako
Noma, Takafumi
author_facet Miyoshi, Keiko
Hagita, Hiroko
Horiguchi, Taigo
Tanimura, Ayako
Noma, Takafumi
author_sort Miyoshi, Keiko
collection PubMed
description Glucosylceramide is the primary molecule of glycosphingolipids, and its metabolic regulation is crucial for life. Defects in the catabolizing enzyme, glucocerebrosidase (GCase), cause a lysosomal storage disorder known as Gaucher disease. However, the genetic regulation of GCase has not been fully understood. Here we show the redefined structure of the GCase coding gene (GBA), and clarify the regulatory mechanisms of its transcription and translation. First, alternative uses of the two GBA gene promoters were identified in fibroblasts and HL60-derived macrophages. Intriguingly, both GBA transcripts and GCase activities were induced in macrophages but not in neutrophils. Second, we observed cap-independent translation occurs via unique internal ribosome entry site activities in first promoter-driven GBA transcripts. Third, the reciprocal expression was observed in GBA and miR22-3p versus GBAP1 transcripts before and after HL60-induced macrophage differentiation. Nevertheless, these findings clearly demonstrate novel cell-type-specific GBA gene expression regulatory mechanisms, providing new insights into GCase biology.
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spelling pubmed-92792972022-07-15 Redefining GBA gene structure unveils the ability of Cap-independent, IRES-dependent gene regulation Miyoshi, Keiko Hagita, Hiroko Horiguchi, Taigo Tanimura, Ayako Noma, Takafumi Commun Biol Article Glucosylceramide is the primary molecule of glycosphingolipids, and its metabolic regulation is crucial for life. Defects in the catabolizing enzyme, glucocerebrosidase (GCase), cause a lysosomal storage disorder known as Gaucher disease. However, the genetic regulation of GCase has not been fully understood. Here we show the redefined structure of the GCase coding gene (GBA), and clarify the regulatory mechanisms of its transcription and translation. First, alternative uses of the two GBA gene promoters were identified in fibroblasts and HL60-derived macrophages. Intriguingly, both GBA transcripts and GCase activities were induced in macrophages but not in neutrophils. Second, we observed cap-independent translation occurs via unique internal ribosome entry site activities in first promoter-driven GBA transcripts. Third, the reciprocal expression was observed in GBA and miR22-3p versus GBAP1 transcripts before and after HL60-induced macrophage differentiation. Nevertheless, these findings clearly demonstrate novel cell-type-specific GBA gene expression regulatory mechanisms, providing new insights into GCase biology. Nature Publishing Group UK 2022-07-13 /pmc/articles/PMC9279297/ /pubmed/35831491 http://dx.doi.org/10.1038/s42003-022-03577-5 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
Miyoshi, Keiko
Hagita, Hiroko
Horiguchi, Taigo
Tanimura, Ayako
Noma, Takafumi
Redefining GBA gene structure unveils the ability of Cap-independent, IRES-dependent gene regulation
title Redefining GBA gene structure unveils the ability of Cap-independent, IRES-dependent gene regulation
title_full Redefining GBA gene structure unveils the ability of Cap-independent, IRES-dependent gene regulation
title_fullStr Redefining GBA gene structure unveils the ability of Cap-independent, IRES-dependent gene regulation
title_full_unstemmed Redefining GBA gene structure unveils the ability of Cap-independent, IRES-dependent gene regulation
title_short Redefining GBA gene structure unveils the ability of Cap-independent, IRES-dependent gene regulation
title_sort redefining gba gene structure unveils the ability of cap-independent, ires-dependent gene regulation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9279297/
https://www.ncbi.nlm.nih.gov/pubmed/35831491
http://dx.doi.org/10.1038/s42003-022-03577-5
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