Oxygen sensing in Drosophila: Multiple isoforms of the prolyl hydroxylase fatiga have different capacity to regulate HIFαSima

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Background: The Hypoxia Inducible Factor (HIF) mediates cellular adaptations to low oxygen. Prolyl-4-hydroxylases are oxygen sensors that hydroxylate the HIF alpha-subunit, promoting its proteasomal degradation in normoxia. Three HIFprolyl hydroxylases, encoded by independent genes, PHD1, PHD2, and...

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Autores principales:	Acevedo, J.M., Centanin, L., Dekanty, A., Wappner, P.
Formato:	Artículo publishedVersion
Lenguaje:	Inglés
Publicado:	2010
Materias:	hypoxia inducible factor oxygenase polyhistidine tag procollagen proline 2 oxoglutarate 4 dioxygenase prolyl 4 hydroxylase 1 prolyl 4 hydroxylase 2 prolyl 4 hydroxylase 3 unclassified drug DNA binding protein Drosophila protein isoenzyme messenger RNA oxygen Sima protein, Drosophila alternative RNA splicing animal cell article cell hypoxia controlled study Drosophila embryo gene expression regulation gene locus gene overexpression imago in vivo study insect cell culture intron loss of function mutation molecular dynamics nonhuman oxygen sensing phenotypic variation protein domain protein localization transcription initiation site transgenics animal anoxia chemistry DNA responsive element Drosophila melanogaster enzymology genetics growth, development and aging human life cycle metabolism protein tertiary structure upregulation Mammalia Alternative Splicing Animals Anoxia DNA-Binding Proteins Drosophila Proteins Gene Expression Regulation, Enzymologic Genetic Loci Humans Isoenzymes Life Cycle Stages Oxygen Procollagen-Proline Dioxygenase Protein Structure, Tertiary Response Elements RNA, Messenger Up-Regulation
Acceso en línea:	http://hdl.handle.net/20.500.12110/paper_19326203_v5_n8_p_Acevedo
Aporte de:	Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) de Universidad de Buenos Aires

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spelling	paperaa:paper_19326203_v5_n8_p_Acevedo2023-06-12T16:51:27Z Oxygen sensing in Drosophila: Multiple isoforms of the prolyl hydroxylase fatiga have different capacity to regulate HIFαSima PLoS ONE 2010;5(8) Acevedo, J.M. Centanin, L. Dekanty, A. Wappner, P. hypoxia inducible factor oxygenase polyhistidine tag procollagen proline 2 oxoglutarate 4 dioxygenase prolyl 4 hydroxylase 1 prolyl 4 hydroxylase 2 prolyl 4 hydroxylase 3 unclassified drug DNA binding protein Drosophila protein isoenzyme messenger RNA oxygen procollagen proline 2 oxoglutarate 4 dioxygenase Sima protein, Drosophila alternative RNA splicing animal cell article cell hypoxia controlled study Drosophila embryo gene expression regulation gene locus gene overexpression imago in vivo study insect cell culture intron loss of function mutation molecular dynamics nonhuman oxygen sensing phenotypic variation protein domain protein localization transcription initiation site transgenics animal anoxia chemistry DNA responsive element Drosophila melanogaster enzymology genetics growth, development and aging human life cycle metabolism protein tertiary structure upregulation Mammalia Alternative Splicing Animals Anoxia DNA-Binding Proteins Drosophila melanogaster Drosophila Proteins Gene Expression Regulation, Enzymologic Genetic Loci Humans Isoenzymes Life Cycle Stages Oxygen Procollagen-Proline Dioxygenase Protein Structure, Tertiary Response Elements RNA, Messenger Up-Regulation Background: The Hypoxia Inducible Factor (HIF) mediates cellular adaptations to low oxygen. Prolyl-4-hydroxylases are oxygen sensors that hydroxylate the HIF alpha-subunit, promoting its proteasomal degradation in normoxia. Three HIFprolyl hydroxylases, encoded by independent genes, PHD1, PHD2, and PHD3, occur in mammals. PHD2, the longest PHD isoform includes a MYND domain, whose biochemical function is unclear. PHD2 and PHD3 genes are induced in hypoxia to shut down HIF dependent transcription upon reoxygenation, while expression of PHD1 is oxygen-independent. The physiologic significance of the diversity of the PHD oxygen sensors is intriguing. Methodology and Principal Findings: We have analyzed the Drosophila PHD locus, fatiga, which encodes 3 isoforms, FgaA, FgaB and FgaC that are originated through a combination of alternative initiation of transcription and alternative splicing. FgaA includes a MYND domain and is homologous to PHD2, while FgaB and FgaC are shorter isoforms most similar to PHD3. Through a combination of genetic experiments in vivo and molecular analyses in cell culture, we show that fgaB but not fgaA is induced in hypoxia, in a Sima-dependent manner, through a HIF-Responsive Element localized in the first intron of fgaA. The regulatory capacity of FgaB is stronger than that of FgaA, as complete reversion of fga loss-of-function phenotypes is observed upon transgenic expression of the former, and only partial rescue occurs after expression of the latter. Conclusions and Significance: Diversity of PHD isoforms is a conserved feature in evolution. As in mammals, there are hypoxia-inducible and non-inducible Drosophila PHDs, and a fly isoform including a MYND domain co-exists with isoforms lacking this domain. Our results suggest that the isoform devoid of a MYND domain has stronger regulatory capacity than that including this domain. Fil:Acevedo, J.M. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Centanin, L. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Dekanty, A. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Wappner, P. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. 2010 info:eu-repo/semantics/article info:ar-repo/semantics/artículo info:eu-repo/semantics/publishedVersion application/pdf eng info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by/2.5/ar http://hdl.handle.net/20.500.12110/paper_19326203_v5_n8_p_Acevedo
institution	Universidad de Buenos Aires
institution_str	I-28
repository_str	R-134
collection	Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA)
language	Inglés
orig_language_str_mv	eng
topic	hypoxia inducible factor oxygenase polyhistidine tag procollagen proline 2 oxoglutarate 4 dioxygenase prolyl 4 hydroxylase 1 prolyl 4 hydroxylase 2 prolyl 4 hydroxylase 3 unclassified drug DNA binding protein Drosophila protein isoenzyme messenger RNA oxygen procollagen proline 2 oxoglutarate 4 dioxygenase Sima protein, Drosophila alternative RNA splicing animal cell article cell hypoxia controlled study Drosophila embryo gene expression regulation gene locus gene overexpression imago in vivo study insect cell culture intron loss of function mutation molecular dynamics nonhuman oxygen sensing phenotypic variation protein domain protein localization transcription initiation site transgenics animal anoxia chemistry DNA responsive element Drosophila melanogaster enzymology genetics growth, development and aging human life cycle metabolism protein tertiary structure upregulation Mammalia Alternative Splicing Animals Anoxia DNA-Binding Proteins Drosophila melanogaster Drosophila Proteins Gene Expression Regulation, Enzymologic Genetic Loci Humans Isoenzymes Life Cycle Stages Oxygen Procollagen-Proline Dioxygenase Protein Structure, Tertiary Response Elements RNA, Messenger Up-Regulation
spellingShingle	hypoxia inducible factor oxygenase polyhistidine tag procollagen proline 2 oxoglutarate 4 dioxygenase prolyl 4 hydroxylase 1 prolyl 4 hydroxylase 2 prolyl 4 hydroxylase 3 unclassified drug DNA binding protein Drosophila protein isoenzyme messenger RNA oxygen procollagen proline 2 oxoglutarate 4 dioxygenase Sima protein, Drosophila alternative RNA splicing animal cell article cell hypoxia controlled study Drosophila embryo gene expression regulation gene locus gene overexpression imago in vivo study insect cell culture intron loss of function mutation molecular dynamics nonhuman oxygen sensing phenotypic variation protein domain protein localization transcription initiation site transgenics animal anoxia chemistry DNA responsive element Drosophila melanogaster enzymology genetics growth, development and aging human life cycle metabolism protein tertiary structure upregulation Mammalia Alternative Splicing Animals Anoxia DNA-Binding Proteins Drosophila melanogaster Drosophila Proteins Gene Expression Regulation, Enzymologic Genetic Loci Humans Isoenzymes Life Cycle Stages Oxygen Procollagen-Proline Dioxygenase Protein Structure, Tertiary Response Elements RNA, Messenger Up-Regulation Acevedo, J.M. Centanin, L. Dekanty, A. Wappner, P. Oxygen sensing in Drosophila: Multiple isoforms of the prolyl hydroxylase fatiga have different capacity to regulate HIFαSima
topic_facet	hypoxia inducible factor oxygenase polyhistidine tag procollagen proline 2 oxoglutarate 4 dioxygenase prolyl 4 hydroxylase 1 prolyl 4 hydroxylase 2 prolyl 4 hydroxylase 3 unclassified drug DNA binding protein Drosophila protein isoenzyme messenger RNA oxygen procollagen proline 2 oxoglutarate 4 dioxygenase Sima protein, Drosophila alternative RNA splicing animal cell article cell hypoxia controlled study Drosophila embryo gene expression regulation gene locus gene overexpression imago in vivo study insect cell culture intron loss of function mutation molecular dynamics nonhuman oxygen sensing phenotypic variation protein domain protein localization transcription initiation site transgenics animal anoxia chemistry DNA responsive element Drosophila melanogaster enzymology genetics growth, development and aging human life cycle metabolism protein tertiary structure upregulation Mammalia Alternative Splicing Animals Anoxia DNA-Binding Proteins Drosophila melanogaster Drosophila Proteins Gene Expression Regulation, Enzymologic Genetic Loci Humans Isoenzymes Life Cycle Stages Oxygen Procollagen-Proline Dioxygenase Protein Structure, Tertiary Response Elements RNA, Messenger Up-Regulation
description	Background: The Hypoxia Inducible Factor (HIF) mediates cellular adaptations to low oxygen. Prolyl-4-hydroxylases are oxygen sensors that hydroxylate the HIF alpha-subunit, promoting its proteasomal degradation in normoxia. Three HIFprolyl hydroxylases, encoded by independent genes, PHD1, PHD2, and PHD3, occur in mammals. PHD2, the longest PHD isoform includes a MYND domain, whose biochemical function is unclear. PHD2 and PHD3 genes are induced in hypoxia to shut down HIF dependent transcription upon reoxygenation, while expression of PHD1 is oxygen-independent. The physiologic significance of the diversity of the PHD oxygen sensors is intriguing. Methodology and Principal Findings: We have analyzed the Drosophila PHD locus, fatiga, which encodes 3 isoforms, FgaA, FgaB and FgaC that are originated through a combination of alternative initiation of transcription and alternative splicing. FgaA includes a MYND domain and is homologous to PHD2, while FgaB and FgaC are shorter isoforms most similar to PHD3. Through a combination of genetic experiments in vivo and molecular analyses in cell culture, we show that fgaB but not fgaA is induced in hypoxia, in a Sima-dependent manner, through a HIF-Responsive Element localized in the first intron of fgaA. The regulatory capacity of FgaB is stronger than that of FgaA, as complete reversion of fga loss-of-function phenotypes is observed upon transgenic expression of the former, and only partial rescue occurs after expression of the latter. Conclusions and Significance: Diversity of PHD isoforms is a conserved feature in evolution. As in mammals, there are hypoxia-inducible and non-inducible Drosophila PHDs, and a fly isoform including a MYND domain co-exists with isoforms lacking this domain. Our results suggest that the isoform devoid of a MYND domain has stronger regulatory capacity than that including this domain.
format	Artículo Artículo publishedVersion
author	Acevedo, J.M. Centanin, L. Dekanty, A. Wappner, P.
author_facet	Acevedo, J.M. Centanin, L. Dekanty, A. Wappner, P.
author_sort	Acevedo, J.M.
title	Oxygen sensing in Drosophila: Multiple isoforms of the prolyl hydroxylase fatiga have different capacity to regulate HIFαSima
title_short	Oxygen sensing in Drosophila: Multiple isoforms of the prolyl hydroxylase fatiga have different capacity to regulate HIFαSima
title_full	Oxygen sensing in Drosophila: Multiple isoforms of the prolyl hydroxylase fatiga have different capacity to regulate HIFαSima
title_fullStr	Oxygen sensing in Drosophila: Multiple isoforms of the prolyl hydroxylase fatiga have different capacity to regulate HIFαSima
title_full_unstemmed	Oxygen sensing in Drosophila: Multiple isoforms of the prolyl hydroxylase fatiga have different capacity to regulate HIFαSima
title_sort	oxygen sensing in drosophila: multiple isoforms of the prolyl hydroxylase fatiga have different capacity to regulate hifαsima
publishDate	2010
url	http://hdl.handle.net/20.500.12110/paper_19326203_v5_n8_p_Acevedo
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_version_	1769810146205106176

Oxygen sensing in Drosophila: Multiple isoforms of the prolyl hydroxylase fatiga have different capacity to regulate HIFαSima

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