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

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Hardy, Serge
Kostantin, Elie
Wang, Shan Jin
Hristova, Tzvetena
Galicia-Vázquez, Gabriela
Baranov, Pavel V.
Pelletier, Jerry
Tremblay, Michel L.
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National Academy of Sciences
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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.
Mg2+ , PRL phosphatase , uORF , PTP4A , mRNA translation , Phosphatase of regenerating liver , Protein tyrosine phosphatase , Magnesium , Metabolism , Untranslated region
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
© 2019, the Authors. Published by the National Academy of Sciences. All rights reserved.