Betaine homocysteine S-methyltransferase emerges as a new player of the nuclear methionine cycle

The paradigm of a cytoplasmic methionine cycle synthesizing/eliminating metabolites that are transported into/out of the nucleus as required has been challenged by detection of significant nuclear levels of several enzymes of this pathway. Here, we show betaine homocysteine S-methyltransferase (BHMT...

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Autores: Pérez-Miguelsanz, Juliana, Vallecillo, Néstor, Garrido, Francisco, Reytor, Edel, Pérez-Sala, Dolores, Pajares, María Ángeles
Tipo de recurso: artículo
Estado:Versión enviada para evaluación y publicación
Fecha de publicación:2017
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/146910
Acceso en línea:http://hdl.handle.net/10261/146910
Access Level:acceso abierto
Palabra clave:Betaine homocysteine methyltransferase
One-carbon metabolism
Cytosolic retention
Galactosamine intoxication
Oxidative stress
Subcellular localization
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spelling Betaine homocysteine S-methyltransferase emerges as a new player of the nuclear methionine cyclePérez-Miguelsanz, JulianaVallecillo, NéstorGarrido, FranciscoReytor, EdelPérez-Sala, DoloresPajares, María ÁngelesBetaine homocysteine methyltransferaseOne-carbon metabolismCytosolic retentionGalactosamine intoxicationOxidative stressSubcellular localizationThe paradigm of a cytoplasmic methionine cycle synthesizing/eliminating metabolites that are transported into/out of the nucleus as required has been challenged by detection of significant nuclear levels of several enzymes of this pathway. Here, we show betaine homocysteine S-methyltransferase (BHMT), an enzyme that exerts a dual function in maintenance of methionine levels and osmoregulation, as a new component of the nuclear branch of the cycle. In most tissues, low expression of Bhmt coincides with a preferential nuclear localization of the protein. Conversely, the liver, with very high Bhmt expression levels, presents a main cytoplasmic localization. Nuclear BHMT is an active homotetramer in normal liver, although the total enzyme activity in this fraction is markedly lower than in the cytosol. N-terminal basic residues play a role in cytoplasmic retention and the ratio of glutathione species regulates nucleocytoplasmic distribution. The oxidative stress associated with D-galactosamine (Gal) or buthionine sulfoximine (BSO) treatments induces BHMT nuclear translocation, an effect that is prevented by administration of N-acetylcysteine (NAC) and glutathione ethyl ester (EGSH), respectively. Unexpectedly, the hepatic nuclear accumulation induced by Gal associates with reduced nuclear BHMT activity and a trend towards increased protein homocysteinylation. Overall, our results support the involvement of BHMT in nuclear homocysteine remethylation, although moonlighting roles unrelated to its enzymatic activity in this compartment cannot be excluded.This work was supported by grants of the Ministerio de Economía y Competitividad (BFU2008-00666 and BFU2009-08977 to MAP; SAF2012-36519 and SAF2015-68590R to DPS) and Instituto de Salud Carlos III (RETIC RIRAAF RD12/0013/0008 and ARADYAL RD16/0006/0021 to DPS).Peer reviewedElsevierMinisterio de Economía y Competitividad (España)Instituto de Salud Carlos IIIConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]201720172017info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Preprintinfo:eu-repo/semantics/submittedVersionhttp://hdl.handle.net/10261/146910reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2015-68590-Rhttps://doi.org/10.1016/j.bbamcr.2017.03.004Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/1469102026-05-22T06:33:51Z
dc.title.none.fl_str_mv Betaine homocysteine S-methyltransferase emerges as a new player of the nuclear methionine cycle
title Betaine homocysteine S-methyltransferase emerges as a new player of the nuclear methionine cycle
spellingShingle Betaine homocysteine S-methyltransferase emerges as a new player of the nuclear methionine cycle
Pérez-Miguelsanz, Juliana
Betaine homocysteine methyltransferase
One-carbon metabolism
Cytosolic retention
Galactosamine intoxication
Oxidative stress
Subcellular localization
title_short Betaine homocysteine S-methyltransferase emerges as a new player of the nuclear methionine cycle
title_full Betaine homocysteine S-methyltransferase emerges as a new player of the nuclear methionine cycle
title_fullStr Betaine homocysteine S-methyltransferase emerges as a new player of the nuclear methionine cycle
title_full_unstemmed Betaine homocysteine S-methyltransferase emerges as a new player of the nuclear methionine cycle
title_sort Betaine homocysteine S-methyltransferase emerges as a new player of the nuclear methionine cycle
dc.creator.none.fl_str_mv Pérez-Miguelsanz, Juliana
Vallecillo, Néstor
Garrido, Francisco
Reytor, Edel
Pérez-Sala, Dolores
Pajares, María Ángeles
author Pérez-Miguelsanz, Juliana
author_facet Pérez-Miguelsanz, Juliana
Vallecillo, Néstor
Garrido, Francisco
Reytor, Edel
Pérez-Sala, Dolores
Pajares, María Ángeles
author_role author
author2 Vallecillo, Néstor
Garrido, Francisco
Reytor, Edel
Pérez-Sala, Dolores
Pajares, María Ángeles
author2_role author
author
author
author
author
dc.contributor.none.fl_str_mv Ministerio de Economía y Competitividad (España)
Instituto de Salud Carlos III
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Betaine homocysteine methyltransferase
One-carbon metabolism
Cytosolic retention
Galactosamine intoxication
Oxidative stress
Subcellular localization
topic Betaine homocysteine methyltransferase
One-carbon metabolism
Cytosolic retention
Galactosamine intoxication
Oxidative stress
Subcellular localization
description The paradigm of a cytoplasmic methionine cycle synthesizing/eliminating metabolites that are transported into/out of the nucleus as required has been challenged by detection of significant nuclear levels of several enzymes of this pathway. Here, we show betaine homocysteine S-methyltransferase (BHMT), an enzyme that exerts a dual function in maintenance of methionine levels and osmoregulation, as a new component of the nuclear branch of the cycle. In most tissues, low expression of Bhmt coincides with a preferential nuclear localization of the protein. Conversely, the liver, with very high Bhmt expression levels, presents a main cytoplasmic localization. Nuclear BHMT is an active homotetramer in normal liver, although the total enzyme activity in this fraction is markedly lower than in the cytosol. N-terminal basic residues play a role in cytoplasmic retention and the ratio of glutathione species regulates nucleocytoplasmic distribution. The oxidative stress associated with D-galactosamine (Gal) or buthionine sulfoximine (BSO) treatments induces BHMT nuclear translocation, an effect that is prevented by administration of N-acetylcysteine (NAC) and glutathione ethyl ester (EGSH), respectively. Unexpectedly, the hepatic nuclear accumulation induced by Gal associates with reduced nuclear BHMT activity and a trend towards increased protein homocysteinylation. Overall, our results support the involvement of BHMT in nuclear homocysteine remethylation, although moonlighting roles unrelated to its enzymatic activity in this compartment cannot be excluded.
publishDate 2017
dc.date.none.fl_str_mv 2017
2017
2017
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Preprint
info:eu-repo/semantics/submittedVersion
format article
status_str submittedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/146910
url http://hdl.handle.net/10261/146910
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv #PLACEHOLDER_PARENT_METADATA_VALUE#
info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2015-68590-R
https://doi.org/10.1016/j.bbamcr.2017.03.004
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,811543

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