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 and Leonard I. Zon ()
Additional contact information
Rebecca A. Wingert: Howard Hughes Medical Institute, Harvard Medical School
Jenna L. Galloway: Howard Hughes Medical Institute, Harvard Medical School
Bruce Barut: Howard Hughes Medical Institute, Harvard Medical School
Helen Foott: Howard Hughes Medical Institute, Harvard Medical School
Paula Fraenkel: Howard Hughes Medical Institute, Harvard Medical School
Jennifer L. Axe: Howard Hughes Medical Institute, Harvard Medical School
Gerhard J. Weber: Howard Hughes Medical Institute, Harvard Medical School
Kimberly Dooley: Howard Hughes Medical Institute, Harvard Medical School
Alan J. Davidson: Howard Hughes Medical Institute, Harvard Medical School
Bettina Schmidt: Howard Hughes Medical Institute, Harvard Medical School
Barry H. Paw: Brigham & Women's Hospital, Harvard Medical School
George C. Shaw: Brigham & Women's Hospital, Harvard Medical School
Paul Kingsley: University of Rochester Medical Center
James Palis: University of Rochester Medical Center
Heidi Schubert: School of Medicine University of Utah
Opal Chen: School of Medicine University of Utah
Jerry Kaplan: School of Medicine University of Utah
Leonard I. Zon: Howard Hughes Medical Institute, Harvard Medical School

Nature, 2005, vol. 436, issue 7053, 1035-1039

Abstract: Abstract Iron is required to produce haem and iron–sulphur (Fe–S) clusters, processes thought to occur independently1,2. 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 genes1,2. 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.

Date: 2005
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DOI: 10.1038/nature03887

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