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

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dc.contributor.authorHardy, Serge
dc.contributor.authorKostantin, Elie
dc.contributor.authorWang, Shan Jin
dc.contributor.authorHristova, Tzvetena
dc.contributor.authorGalicia-Vázquez, Gabriela
dc.contributor.authorBaranov, Pavel V.
dc.contributor.authorPelletier, Jerry
dc.contributor.authorTremblay, Michel L.
dc.contributor.funderCanadian Institutes of Health Researchen
dc.contributor.funderScience Foundation Irelanden
dc.contributor.funderHealth Research Boarden
dc.contributor.funderWellcome Trusten
dc.date.accessioned2019-03-07T10:07:36Z
dc.date.available2019-03-07T10:07:36Z
dc.date.issued2019-02-19
dc.date.updated2019-03-07T09:47:34Z
dc.description.abstractThe 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.sponsorshipCanadian 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.description.statusPeer revieweden
dc.description.versionAccepted Versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.citationHardy, 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.1815361116en
dc.identifier.doi10.1073/pnas.1815361116
dc.identifier.endpage2934en
dc.identifier.issn0027-8424
dc.identifier.issn1091-6490
dc.identifier.issued8en
dc.identifier.journaltitleProceedings of the National Academy of Sciences of the United States of Americaen
dc.identifier.startpage2925en
dc.identifier.urihttps://hdl.handle.net/10468/7568
dc.identifier.volume116en
dc.language.isoenen
dc.publisherNational Academy of Sciencesen
dc.relation.urihttps://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.subjectMg2+en
dc.subjectPRL phosphataseen
dc.subjectuORFen
dc.subjectPTP4Aen
dc.subjectmRNA translationen
dc.subjectPhosphatase of regenerating liveren
dc.subjectProtein tyrosine phosphataseen
dc.subjectMagnesiumen
dc.subjectMetabolismen
dc.subjectUntranslated regionen
dc.titleMagnesium-sensitive upstream ORF controls PRL phosphatase expression to mediate energy metabolismen
dc.typeArticle (peer-reviewed)en
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