Magnesium-sensitive upstream ORF controls PRL phosphatase expression to mediate energy metabolism

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dc.contributor.author Hardy, Serge
dc.contributor.author Kostantin, Elie
dc.contributor.author Wang, Shan Jin
dc.contributor.author Hristova, Tzvetena
dc.contributor.author Galicia-Vázquez, Gabriela
dc.contributor.author Baranov, Pavel V.
dc.contributor.author Pelletier, Jerry
dc.contributor.author Tremblay, Michel L.
dc.date.accessioned 2019-03-07T10:07:36Z
dc.date.available 2019-03-07T10:07:36Z
dc.date.issued 2019-02-19
dc.identifier.citation Hardy, S., Kostantin, E., Wang, S. J., Hristova, T., Galicia-Vázquez, G., Baranov, P. V., Pelletier, J. and Tremblay, M. L. (2019) 'Magnesium-sensitive upstream ORF controls PRL phosphatase expression to mediate energy metabolism', Proceedings of the National Academy of Sciences of the United States of America, 116(8), pp. 2925-2934. doi:10.1073/pnas.1815361116 en
dc.identifier.volume 116 en
dc.identifier.issued 8 en
dc.identifier.startpage 2925 en
dc.identifier.endpage 2934 en
dc.identifier.issn 0027-8424
dc.identifier.issn 1091-6490
dc.identifier.uri http://hdl.handle.net/10468/7568
dc.identifier.doi 10.1073/pnas.1815361116
dc.description.abstract The phosphatases of regenerative liver (PRL) have been shown to interact with the CNNM magnesium transport regulators. Through this protein complex, PRL controls the levels of intracellular magnesium. Our study uncovers a remarkable posttranscriptional feedback mechanism by which magnesium controls PRL expression in mammalian cells. Here we show that regulation of PRL mRNA translation by magnesium depends on a 5'UTR-located upstream ORF, which is conserved among all vertebrates, proposing an evolutionary molecular mechanism of action by a divalent ion. This magnesium-sensing mechanism, which also involves the key metabolic sensor AMPK, is thus central to maintain cellular homeostasis in mammalian cells.Phosphatases of regenerating liver (PRL-1, PRL-2, and PRL-3, also known as PTP4A1, PTP4A2, and PTP4A3) control magnesium homeostasis through an association with the CNNM magnesium transport regulators. Although high PRL levels have been linked to cancer progression, regulation of their expression is poorly understood. Here we show that modulating intracellular magnesium levels correlates with a rapid change of PRL expression by a mechanism involving its 5'UTR mRNA region. Mutations or CRISPR-Cas9 targeting of the conserved upstream ORF present in the mRNA leader derepress PRL protein synthesis and attenuate the translational response to magnesium levels. Mechanistically, magnesium depletion reduces intracellular ATP but up-regulates PRL protein expression via activation of the AMPK/mTORC2 pathway, which controls cellular energy status. Hence, altered PRL-2 expression leads to metabolic reprogramming of the cells. These findings uncover a magnesium-sensitive mechanism controlling PRL expression, which plays a role in cellular bioenergetics. en
dc.description.sponsorship Canadian Institutes of Health Research (Grants MOP-142497 and FDN-159923); Science Foundation Ireland–Health Research Board–Wellcome Trust (Biomedical Research Partnership Investigator Award in Science 210692/Z/18/Z) en
dc.format.mimetype application/pdf en
dc.language.iso en en
dc.publisher National Academy of Sciences en
dc.relation.uri https://www.pnas.org/content/pnas/116/8/2925.full.pdf
dc.rights © 2019, the Authors. Published by the National Academy of Sciences. All rights reserved. en
dc.subject Mg2+ en
dc.subject PRL phosphatase en
dc.subject uORF en
dc.subject PTP4A en
dc.subject mRNA translation en
dc.subject Phosphatase of regenerating liver en
dc.subject Protein tyrosine phosphatase en
dc.subject Magnesium en
dc.subject Metabolism en
dc.subject Untranslated region en
dc.title Magnesium-sensitive upstream ORF controls PRL phosphatase expression to mediate energy metabolism en
dc.type Article (peer-reviewed) en
dc.internal.authorcontactother Pavel Baranov, School Of Biochemistry & Cell Biology, University College Cork, Cork, Ireland. +353-21-490-3000 Email: p.baranov@ucc.ie en
dc.internal.availability Full text available en
dc.date.updated 2019-03-07T09:47:34Z
dc.description.version Accepted Version en
dc.internal.rssid 476619892
dc.contributor.funder Canadian Institutes of Health Research en
dc.contributor.funder Science Foundation Ireland en
dc.contributor.funder Health Research Board en
dc.contributor.funder Wellcome Trust en
dc.description.status Peer reviewed en
dc.identifier.journaltitle Proceedings of the National Academy of Sciences of the United States of America en
dc.internal.copyrightchecked Yes en
dc.internal.licenseacceptance Yes en
dc.internal.IRISemailaddress p.baranov@ucc.ie en


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