Deficiency of glutaredoxin 5 reveals Fe-S clusters are required for vertebrate haem synthesis

Rebecca A. Wingert, Jenna L. Galloway, Bruce Barut, Helen Foott, Paula Fraenkel, Jennifer L. Axe, Gerhard J. Weber, Kimberly Dooley, Alan J. Davidson, Bettina Schmidt, Barry H. Paw, George C. Shaw, Paul Kingsley, James Palis, Heidi Schubert, Opal Chen, Jerry Kaplan, Leonard I. Zon, F. van Bebber, E. Busch-NentwichR. Dahm, H. G. Frohnhöfer, H. Geiger, D. Gilmour, S. Holley, J. Hooge, D. Jülich, H. Knaut, F. Maderspacher, C. Neumann, T. Nicolson, C. Nüsslein-Volhard, H. Roehl, U. Schönberger, C. Seiler, C. Söllner, M. Sonawane, A. Wehner, C. Weiler, U. Hagner, E. Hennen, C. Kaps, A. Kirchner, T. I. Koblizek, U. Langheinrich, C. Metzger, R. Nordin, M. Pezzuti, K. Schlombs, J. deSantana-Stamm, T. Trowe, G. Vacun, A. Walker, C. Weiler

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Abstract

Iron is required to produce haem and iron-sulphur (Fe-S) clusters, processes thought to occur independently. Here we show that the hypochromic anaemia in shiraz (sir) zebrafish mutants is caused by deficiency of glutaredoxin 5 (grx5), a gene required in yeast for Fe-S cluster assembly. We found that grx5 was expressed in erythroid cells of zebrafish and mice. Zebrafish grx5 rescued the assembly of Δgrx5 yeast Fe-S, showing that the biochemical function of grx5 is evolutionarily conserved. In contrast to yeast, vertebrates use iron regulatory protein 1 (IRP1) to sense intracellular iron and regulate mRNA stability or the translation of iron metabolism genes. We found that loss of Fe-S cluster assembly in sir animals activated IRP1 and blocked haem biosynthesis catalysed by aminolaevulinate synthase 2 (ALAS2). Overexpression of ALAS2 RNA without the 5′ iron response element that binds IRP1 rescued sir embryos, whereas overexpression of ALAS2 including the iron response element did not. Further, antisense knockdown of IRP1 restored sir embryo haemoglobin synthesis. These findings uncover a connection between haem biosynthesis and Fe-S clusters, indicating that haemoglobin production in the differentiating red cell is regulated through Fe-S cluster assembly.

Original languageEnglish (US)
Pages (from-to)1035-1039
Number of pages5
JournalNature
Volume436
Issue number7053
DOIs
StatePublished - Aug 18 2005

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Wingert, R. A., Galloway, J. L., Barut, B., Foott, H., Fraenkel, P., Axe, J. L., Weber, G. J., Dooley, K., Davidson, A. J., Schmidt, B., Paw, B. H., Shaw, G. C., Kingsley, P., Palis, J., Schubert, H., Chen, O., Kaplan, J., Zon, L. I., van Bebber, F., ... Weiler, C. (2005). Deficiency of glutaredoxin 5 reveals Fe-S clusters are required for vertebrate haem synthesis. Nature, 436(7053), 1035-1039. https://doi.org/10.1038/nature03887