FAM210B is an erythropoietin target and regulates erythroid heme synthesis by controlling mitochondrial iron import and ferrochelatase activity

Yvette Y. Yien, Jiahai Shi, Caiyong Chen, Jesmine T.M. Cheung, Anthony S. Grillo, Rishna Shrestha, Liangtao Li, Xuedi Zhang, Martin D. Kafina, Paul D. Kingsley, Matthew J. King, Julien Ablain, Hojun Li, Leonard I. Zon, James Palis, Martin D. Burke, Daniel E. Bauer, Stuart H. Orkin, Carla M. Koehler, John D. PhillipsJerry Kaplan, Diane M. Ward, Harvey F. Lodish, Barry H. Paw

Research output: Contribution to journalArticle

Abstract

Erythropoietin (EPO) signaling is critical to many processes essential to terminal erythropoiesis. Despite the centrality of iron metabolism to erythropoiesis, the mechanisms by which EPO regulates iron status are not well-understood. To this end, here we profiled gene expression in EPO-treated 32D pro-B cells and developing fetal liver erythroid cells to identify additional iron regulatory genes. We determined that FAM210B, a mitochondrial inner-membrane protein, is essential for hemoglobinization, proliferation, and enucleation during terminal erythroid maturation. Fam210b deficiency led to defects in mitochondrial iron uptake, heme synthesis, and iron-sulfur cluster formation. These defects were corrected with a lipid-soluble, small-molecule iron transporter, hinokitiol, in Fam210b-deficient murine erythroid cells and zebrafish morphants. Genetic complementation experiments revealed that FAM210B is not a mitochondrial iron transporter but is required for adequate mitochondrial iron import to sustain heme synthesis and iron-sulfur cluster formation during erythroid differentiation. FAM210B was also required for maximal ferrochelatase activity in differentiating erythroid cells.Wepropose thatFAM210Bfunctions as an adaptor protein that facilitates the formation of an oligomeric mitochondrial iron transport complex, required for the increase in iron acquisition forhemesynthesis during terminal erythropoiesis. Collectively, our results reveal a critical mechanism by whichEPOsignaling regulates terminal erythropoiesis and iron metabolism.

Original languageEnglish (US)
Pages (from-to)19797-19811
Number of pages15
JournalJournal of Biological Chemistry
Volume293
Issue number51
DOIs
StatePublished - Jan 1 2018

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Ferrochelatase
Erythropoietin
Heme
Iron
Erythropoiesis
Erythroid Cells
Sulfur
Metabolism
Defects
B-Lymphoid Precursor Cells
Zebrafish
Regulator Genes
Gene expression
Liver

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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FAM210B is an erythropoietin target and regulates erythroid heme synthesis by controlling mitochondrial iron import and ferrochelatase activity. / Yien, Yvette Y.; Shi, Jiahai; Chen, Caiyong; Cheung, Jesmine T.M.; Grillo, Anthony S.; Shrestha, Rishna; Li, Liangtao; Zhang, Xuedi; Kafina, Martin D.; Kingsley, Paul D.; King, Matthew J.; Ablain, Julien; Li, Hojun; Zon, Leonard I.; Palis, James; Burke, Martin D.; Bauer, Daniel E.; Orkin, Stuart H.; Koehler, Carla M.; Phillips, John D.; Kaplan, Jerry; Ward, Diane M.; Lodish, Harvey F.; Paw, Barry H.

In: Journal of Biological Chemistry, Vol. 293, No. 51, 01.01.2018, p. 19797-19811.

Research output: Contribution to journalArticle

Yien, YY, Shi, J, Chen, C, Cheung, JTM, Grillo, AS, Shrestha, R, Li, L, Zhang, X, Kafina, MD, Kingsley, PD, King, MJ, Ablain, J, Li, H, Zon, LI, Palis, J, Burke, MD, Bauer, DE, Orkin, SH, Koehler, CM, Phillips, JD, Kaplan, J, Ward, DM, Lodish, HF & Paw, BH 2018, 'FAM210B is an erythropoietin target and regulates erythroid heme synthesis by controlling mitochondrial iron import and ferrochelatase activity', Journal of Biological Chemistry, vol. 293, no. 51, pp. 19797-19811. https://doi.org/10.1074/jbc.RA118.002742
Yien, Yvette Y. ; Shi, Jiahai ; Chen, Caiyong ; Cheung, Jesmine T.M. ; Grillo, Anthony S. ; Shrestha, Rishna ; Li, Liangtao ; Zhang, Xuedi ; Kafina, Martin D. ; Kingsley, Paul D. ; King, Matthew J. ; Ablain, Julien ; Li, Hojun ; Zon, Leonard I. ; Palis, James ; Burke, Martin D. ; Bauer, Daniel E. ; Orkin, Stuart H. ; Koehler, Carla M. ; Phillips, John D. ; Kaplan, Jerry ; Ward, Diane M. ; Lodish, Harvey F. ; Paw, Barry H. / FAM210B is an erythropoietin target and regulates erythroid heme synthesis by controlling mitochondrial iron import and ferrochelatase activity. In: Journal of Biological Chemistry. 2018 ; Vol. 293, No. 51. pp. 19797-19811.
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AU - Yien, Yvette Y.

AU - Shi, Jiahai

AU - Chen, Caiyong

AU - Cheung, Jesmine T.M.

AU - Grillo, Anthony S.

AU - Shrestha, Rishna

AU - Li, Liangtao

AU - Zhang, Xuedi

AU - Kafina, Martin D.

AU - Kingsley, Paul D.

AU - King, Matthew J.

AU - Ablain, Julien

AU - Li, Hojun

AU - Zon, Leonard I.

AU - Palis, James

AU - Burke, Martin D.

AU - Bauer, Daniel E.

AU - Orkin, Stuart H.

AU - Koehler, Carla M.

AU - Phillips, John D.

AU - Kaplan, Jerry

AU - Ward, Diane M.

AU - Lodish, Harvey F.

AU - Paw, Barry H.

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N2 - Erythropoietin (EPO) signaling is critical to many processes essential to terminal erythropoiesis. Despite the centrality of iron metabolism to erythropoiesis, the mechanisms by which EPO regulates iron status are not well-understood. To this end, here we profiled gene expression in EPO-treated 32D pro-B cells and developing fetal liver erythroid cells to identify additional iron regulatory genes. We determined that FAM210B, a mitochondrial inner-membrane protein, is essential for hemoglobinization, proliferation, and enucleation during terminal erythroid maturation. Fam210b deficiency led to defects in mitochondrial iron uptake, heme synthesis, and iron-sulfur cluster formation. These defects were corrected with a lipid-soluble, small-molecule iron transporter, hinokitiol, in Fam210b-deficient murine erythroid cells and zebrafish morphants. Genetic complementation experiments revealed that FAM210B is not a mitochondrial iron transporter but is required for adequate mitochondrial iron import to sustain heme synthesis and iron-sulfur cluster formation during erythroid differentiation. FAM210B was also required for maximal ferrochelatase activity in differentiating erythroid cells.Wepropose thatFAM210Bfunctions as an adaptor protein that facilitates the formation of an oligomeric mitochondrial iron transport complex, required for the increase in iron acquisition forhemesynthesis during terminal erythropoiesis. Collectively, our results reveal a critical mechanism by whichEPOsignaling regulates terminal erythropoiesis and iron metabolism.

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