Thyroid hormone receptor beta and NCOA4 regulate terminal erythrocyte differentiation

Gao, Xiaofei; Lee, Hsiang Ying; Li, Wenbo; Platt, Randall J.; Barrasa, M. Inmaculada; Ma, Qi; Elmes, Russell R.; Rosenfeld, Michael G.; Lodish, Harvey F.

doi:10.1073/pnas.1711058114

Cited by 41 publications

(51 citation statements)

References 49 publications

(71 reference statements)

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“…First, NCOA4 is expressed at high levels in maturing orthocromatic erythroblasts (7); second, in vitro (4,8) and ex vivo data (9) suggest that NCOA4 is required for erythroid cells differentiation and hemoglobinization, modulating iron incorporation into heme. An erythropoietic role for NCOA4 was suggested also in vivo in zebrafish embryos treated with morpholinos to Ncoa4 (4).…”

Section: Introductionmentioning

confidence: 99%

NCOA4-mediated ferritinophagy in macrophages is crucial to sustain erythropoiesis in mice

et al. 2020

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The Nuclear Receptor Coactivator 4 (NCOA4) promotes ferritin degradation and Ncoa4-ko mice in C57BL/6 background show microcytosis and mild anemia, aggravated by iron deficiency. To understand tissue specific contribution of NCOA4-mediated ferritinophagy we explored the effect of Ncoa4 genetic ablation in the iron-rich strain Sv129/J. Increased body iron content protects mice from anemia and, in basal conditions, Sv129/J Ncoa4-ko mice show only microcytosis; nevertheless, when fed a low-iron diet they develop a more severe anemia compared to wild-type animals. Reciprocal bone marrow (BM) transplantation from wild-type donors into Ncoa4-ko and from Ncoa4-ko into wild-type mice revealed that microcytosis and susceptibility to iron deficiency anemia depend on BM-derived cells. Erythropoiesis reconstitution with RBC count and hemoglobin normalization occurred at the same rate in transplanted animals independently of the genotype. Importantly, NCOA4 loss did not affect terminal erythropoiesis in iron deficiency, both in total and specific BM Ncoa4-ko animals compared to controls. On the contrary, upon a low iron diet, spleen from wild-type animals with Ncoa4-ko BM displayed marked iron retention compared to (wild-type BM) controls, indicating defective macrophage iron release in the former. Thus, EPO administration failed to mobilize iron from stores in Ncoa4-ko animals. Furthermore, Ncoa4 inactivation in thalassemic mice did not worsen the hematological phenotype. Overall our data reveal a major role for NCOA4-mediated ferritinophagy in macrophages to favor iron release for erythropoiesis, especially in iron deficiency.

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Section: Introductionmentioning

confidence: 99%

NCOA4-mediated ferritinophagy in macrophages is crucial to sustain erythropoiesis in mice

et al. 2020

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“…This suggests that mice unable to efficiently degrade ferritin may eventually develop an 'overflow' of iron into the cytoplasm leading to higher susceptibility to oxidative damage as discussed in greater detail below. NCOA4 appears to be more important at various stages of development as NCOA4 KO mice examined at the immediate postnatal period showed a more severe anemia [34]. This study suggests a differential temporal requirement of NCOA4-mediated ferritinophagy in periods of high iron demand.…”

Section: Ncoa4 Mediates Ferritin Iron Release To Support Erythropoiesismentioning

confidence: 63%

“…Subsequent studies suggested that NCOA4 also regulated a number of additional nuclear receptors [29][30][31][32][33]. A recent study suggested that NCOA4 can be regulated by thyroid hormone, promoting NCOA4 recruitment to chromatin regions that induce a transcriptional program supporting erythropoiesis [34]. Finally, Bellelli et al suggest NCOA4 inhibits DNA replication origin activation by binding to the MCM2-7…”

Section: Ncoa4 Mediates Ferritin Transport To the Lysosome For Degradmentioning

confidence: 99%

“…Furthermore, results from Gao et al suggest there might be a temporal variation in NCOA4 dependency[34], with a higher reliance at early developmental stages. Defining the importance of NCOA4 at different developmental stages as well as comparing acute vs. longterm KO will be key to understanding the mechanisms triggered in erythrocytes or other cell types to compensate for NCOA4 loss.…”

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confidence: 99%

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The Role of NCOA4-Mediated Ferritinophagy in Iron Homeostasis

Santana-Codina¹,

Mancias²

2018

Preprint

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Nuclear receptor coactivator 4 (NCOA4) is a selective cargo receptor that mediates the autophagic degradation of ferritin (“ferritinophagy”), the cytosolic iron storage complex. NCOA4-mediated ferritinophagy maintains intracellular iron homeostasis by facilitating ferritin iron storage or release according to demand. Ferritinophagy is involved in iron-dependent physiological processes such as erythropoiesis, where NCOA4 mediates ferritin iron release for mitochondrial heme synthesis. Recently, ferritinophagy has been shown to regulate ferroptosis, a newly described form of iron-dependent cell death mediated by excess lipid peroxidation. Dysregulation of iron metabolism and ferroptosis have been described in neurodegeneration, cancer, and infection, but little is known about the role of ferritinophagy in the pathogenesis of these diseases. Here, we will review the biochemical regulation of NCOA4, its contribution to physiological processes and its role in disease. Finally, we will discuss the potential of activating or inhibiting ferritinophagy and ferroptosis for therapeutic purposes.

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“…More broadly, with respect to the role of Ncoa4 in modulating the response to acute erythropoietic stressors, we refer Nai and colleagues to multiple prior published studies showing that genetic ablation of Ncoa4 affects erythropoiesis acutely, including our own work in an orthogonal zebrafish model. 8,9 Furthermore, we note our findings in our erythroid specific Ncoa4 knockout model (Ncoa4 fl/fl ; EpoR-Cre) where these animals have an increased sensitivity to acute erythropoietic stress upon phenylhydrazine-induced anemia and have an extrareliance on compensatory mechanisms to support full recovery of an anemia. These findings all support our conclusions regarding the role of Ncoa4 in supporting erythropoiesis.…”

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confidence: 65%

The role of nuclear receptor co-activator 4 in erythropoiesis (Reply to Nai et al.)

et al. 2019

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We thank Nai and colleagues for their interest in our recently published paper, Santana-Codina et al., 1 and their comment, also published in Haematologica. 2 Their comment, containing new unpublished experimental data, questions the importance of nuclear receptor coactivator 4 (NCOA4) in acute erythropoietic expansion. Here, we respond to clarify inconsistencies in the interpretation of their new data with respect to our experiments and highlight the multiple lines of evidence that support our overall conclusions regarding the cell autonomous and non-autonomous roles of NCOA4 in supporting murine erythropoiesis. With respect to their concerns over the use of tamoxifen in our inducible model of acute whole body Ncoa4 genetic ablation: we stand by the conclusions of our experiments as they were tightly controlled with all appropriate genetic backgrounds and treatment controls utilized. While we agree that tamoxifen may have off-target effects on red blood cells (RBC), our experiments as designed and carried out were well-controlled. Specifically, mice in each group had no baseline alterations in systemic iron parameters or erythropoiesis prior to tamoxifen administration making the alterations observed most likely to be a result of acute Ncoa4 ablation leading to an acute loss of flux of ferritin through the autophagic degradation pathway thereby altering systemic iron homeostasis and basal erythropoiesis. The key difference in the new data presented by Nai and colleagues in their comment 2 is the presence of long-standing Ncoa4 knockout in their mouse model prior to administration of tamoxifen, which we argue makes their conclusions uninterpretable with respect to our data in an inducible knockout mouse model. Specifically, they use a mouse model with constitutive (from birth) total body knockout of Ncoa4, which is a distinct situation compared to acute ablation of Ncoa4 expression in an adult mice. The critical point here is that with a constitutive total body ablation of Ncoa4 from birth, erythropoiesis is altered in such a way that RBC at the time of tamoxifen administration already have accumulated long-standing significant changes that alter the baseline response to any agent that has potential deleterious effects on the RBC, such as tamoxifen. For that matter, Nai et al. do not present hemoglobin levels in wild-type mice that were subjected to gavage solely with the vehicle (corn oil) that was used to dissolve tamoxifen. Given that repeated gavage is expected to induce a profound stress response, it is unclear if the reduction in hemoglobin levels observed in wild type mice (and which form the basis of their arguments) can be attributed specifically to tamoxifen. While we cannot fully evaluate their claim regarding the lack of alterations in systemic iron parameters in the Sv129/J background they use given their reference to unpublished data, we do note that these Ncoa4 knockout animals appear to have altered baseline hematologic parameters with microcytosis and a trend towards decreased hemogolobin and he...

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Thyroid hormone receptor beta and NCOA4 regulate terminal erythrocyte differentiation

Cited by 41 publications

References 49 publications

NCOA4-mediated ferritinophagy in macrophages is crucial to sustain erythropoiesis in mice

NCOA4-mediated ferritinophagy in macrophages is crucial to sustain erythropoiesis in mice

The Role of NCOA4-Mediated Ferritinophagy in Iron Homeostasis

The role of nuclear receptor co-activator 4 in erythropoiesis (Reply to Nai et al.)

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