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 language | English (US) |
|---|---|
| Pages (from-to) | 19797-19811 |
| Number of pages | 15 |
| Journal | Journal of Biological Chemistry |
| Volume | 293 |
| Issue number | 51 |
| DOIs | |
| State | Published - Jan 1 2018 |
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ASJC Scopus subject areas
- Biochemistry
- Molecular Biology
- Cell Biology
Cite this
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 journal › Article
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TY - JOUR
T1 - FAM210B is an erythropoietin target and regulates erythroid heme synthesis by controlling mitochondrial iron import and ferrochelatase activity
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.
PY - 2018/1/1
Y1 - 2018/1/1
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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85058915163&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85058915163&partnerID=8YFLogxK
U2 - 10.1074/jbc.RA118.002742
DO - 10.1074/jbc.RA118.002742
M3 - Article
C2 - 30366982
AN - SCOPUS:85058915163
VL - 293
SP - 19797
EP - 19811
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 51
ER -