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-Nentwich; R. 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

doi:10.1038/nature03887

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 language	English (US)
Pages (from-to)	1035-1039
Number of pages	5
Journal	Nature
Volume	436
Issue number	7053
DOIs	https://doi.org/10.1038/nature03887
State	Published - Aug 18 2005
Externally published	Yes

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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

Wingert, RA, Galloway, JL, Barut, B, Foott, H, Fraenkel, P, Axe, JL, Weber, GJ, Dooley, K, Davidson, AJ, Schmidt, B, Paw, BH, Shaw, GC, Kingsley, P, Palis, J, Schubert, H, Chen, O, Kaplan, J, Zon, LI, van Bebber, F, Busch-Nentwich, E, Dahm, R, Frohnhöfer, HG, Geiger, H, Gilmour, D, Holley, S, Hooge, J, Jülich, D, Knaut, H, Maderspacher, F, Neumann, C, Nicolson, T, Nüsslein-Volhard, C, Roehl, H, Schönberger, U, Seiler, C, Söllner, C, Sonawane, M, Wehner, A, Weiler, C, Hagner, U, Hennen, E, Kaps, C, Kirchner, A, Koblizek, TI, Langheinrich, U, Metzger, C, Nordin, R, Pezzuti, M, Schlombs, K, deSantana-Stamm, J, Trowe, T, Vacun, G, Walker, A & Weiler, C 2005, 'Deficiency of glutaredoxin 5 reveals Fe-S clusters are required for vertebrate haem synthesis', Nature, vol. 436, no. 7053, pp. 1035-1039. https://doi.org/10.1038/nature03887

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title = "Deficiency of glutaredoxin 5 reveals Fe-S clusters are required for vertebrate haem synthesis",

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.",

author = "Wingert, {Rebecca A.} and Galloway, {Jenna L.} and Bruce Barut and Helen Foott and Paula Fraenkel and Axe, {Jennifer L.} and Weber, {Gerhard J.} and Kimberly Dooley and Davidson, {Alan J.} and Bettina Schmidt and Paw, {Barry H.} and Shaw, {George C.} and Paul Kingsley and James Palis and Heidi Schubert and Opal Chen and Jerry Kaplan and Zon, {Leonard I.} and {van Bebber}, F. and E. Busch-Nentwich and R. Dahm and Frohnh{\"o}fer, {H. G.} and H. Geiger and D. Gilmour and S. Holley and J. Hooge and D. J{\"u}lich and H. Knaut and F. Maderspacher and C. Neumann and T. Nicolson and C. N{\"u}sslein-Volhard and H. Roehl and U. Sch{\"o}nberger and C. Seiler and C. S{\"o}llner and M. Sonawane and A. Wehner and C. Weiler and U. Hagner and E. Hennen and C. Kaps and A. Kirchner and Koblizek, {T. I.} and U. Langheinrich and C. Metzger and R. Nordin and M. Pezzuti and K. Schlombs and J. deSantana-Stamm and T. Trowe and G. Vacun and A. Walker and C. Weiler",

year = "2005",

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doi = "10.1038/nature03887",

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T1 - Deficiency of glutaredoxin 5 reveals Fe-S clusters are required for vertebrate haem synthesis

AU - Wingert, Rebecca A.

AU - Galloway, Jenna L.

AU - Barut, Bruce

AU - Foott, Helen

AU - Fraenkel, Paula

AU - Axe, Jennifer L.

AU - Weber, Gerhard J.

AU - Dooley, Kimberly

AU - Davidson, Alan J.

AU - Schmidt, Bettina

AU - Paw, Barry H.

AU - Shaw, George C.

AU - Kingsley, Paul

AU - Palis, James

AU - Schubert, Heidi

AU - Chen, Opal

AU - Kaplan, Jerry

AU - Zon, Leonard I.

AU - van Bebber, F.

AU - Busch-Nentwich, E.

AU - Dahm, R.

AU - Frohnhöfer, H. G.

AU - Geiger, H.

AU - Gilmour, D.

AU - Holley, S.

AU - Hooge, J.

AU - Jülich, D.

AU - Knaut, H.

AU - Maderspacher, F.

AU - Neumann, C.

AU - Nicolson, T.

AU - Nüsslein-Volhard, C.

AU - Roehl, H.

AU - Schönberger, U.

AU - Seiler, C.

AU - Söllner, C.

AU - Sonawane, M.

AU - Wehner, A.

AU - Weiler, C.

AU - Hagner, U.

AU - Hennen, E.

AU - Kaps, C.

AU - Kirchner, A.

AU - Koblizek, T. I.

AU - Langheinrich, U.

AU - Metzger, C.

AU - Nordin, R.

AU - Pezzuti, M.

AU - Schlombs, K.

AU - deSantana-Stamm, J.

AU - Trowe, T.

AU - Vacun, G.

AU - Walker, A.

AU - Weiler, C.

PY - 2005/8/18

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N2 - 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.

AB - 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.

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

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