Lobe specificity of iron binding to transferrin modulates murine erythropoiesis and iron homeostasis

Parrow, Nermi L.; Feola, Maria; Guerra, Amaliris; Casu, Carla; Prasad, Princy; Mammen, Luke; Ali, Faris; Vaicikauskas, Edvinas; Rivella, Stefano; Ginzburg, Yelena; Fleming, Robert E.

doi:10.1182/blood.2018893099

Cited by 38 publications

(29 citation statements)

References 53 publications

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“…Parrow et al recently reported that mice carrying mutations in Trf that prevent iron binding at either lobe have hepatocellular iron overload and decreased liver expression of the iron regulatory hormone hepcidin. 3 These findings provide further support that Trf plays a key role in iron homeostasis and erythropoiesis.…”

Section: Introductionsupporting

confidence: 53%

Hepatic transferrin plays a role in systemic iron homeostasis and liver ferroptosis

Jiang

Wang

et al. 2020

Blood

363

240

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Although the serum-abundant metal-binding protein transferrin (encoded by the Trf gene) is synthesized primarily in the liver, its function in the liver is largely unknown. Here, we generated hepatocyte-specific Trf knockout mice (Trf-LKO), which are viable and fertile but have impaired erythropoiesis and altered iron metabolism. Moreover, feeding Trf-LKO mice a high-iron diet increased their susceptibility to develop ferroptosis-induced liver fibrosis. Importantly, we found that treating Trf-LKO mice with the ferroptosis inhibitor ferrostatin-1 potently rescued liver fibrosis induced by either high dietary iron or carbon tetrachloride (CCl4) injections. In addition, deleting hepatic Slc39a14 expression in Trf-LKO mice significantly reduced hepatic iron accumulation, thereby reducing ferroptosis-mediated liver fibrosis induced by either high dietary iron diet or CCl4 injections. Finally, we found that patients with liver cirrhosis have significantly lower levels of serum transferrin and hepatic transferrin, as well as higher levels of hepatic iron and lipid peroxidation compared to healthy controls. Taken together, these data indicate that hepatic transferrin plays a protective role in maintaining liver function, providing a possible therapeutic target for preventing ferroptosis-induced liver fibrosis.

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Section: Introductionsupporting

confidence: 53%

Hepatic transferrin plays a role in systemic iron homeostasis and liver ferroptosis

Jiang

Wang

et al. 2020

Blood

363

240

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“…Both receptors present little to no affinity for Apo-Tf at pH 7.4. Partially saturated transferrin can be found in the circulation [ 32 ], ferric ions binding first to the C-terminal lobe of Tf [ 33 ]. Rabbit TFR1 can bind partially saturated transferrin although its affinity for C-lobe saturated transferrin and N-lobe saturated transferrin is only five times and six times greater than for Apo-Tf [ 34 ].…”

Section: Regulation Of the Transferrin Receptors In Erythroid Cellmentioning

confidence: 99%

“…Aside from its own signaling, TFR2 may also affect EPOR signaling in erythroid cells by regulating EPOR cell surface expression [ 32 , 55 ]. Forejtnikovà et al demonstrated that TFR2 and EPOR associate in the endoplasmic reticulum of erythroblasts and that TFR2 then facilitates the transport of EPOR to cell surface.…”

Section: Signaling Of the Transferrin Receptors And Erythropoiesismentioning

confidence: 99%

Transferrin Receptors in Erythropoiesis

Richard

Verdier

2020

IJMS

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Erythropoiesis is a highly dynamic process giving rise to red blood cells from hematopoietic stem cells present in the bone marrow. Red blood cells transport oxygen to tissues thanks to the hemoglobin comprised of α- and β-globin chains and of iron-containing hemes. Erythropoiesis is the most iron-consuming process to support hemoglobin production. Iron delivery is mediated via transferrin internalization by the endocytosis of transferrin receptor type 1 (TFR1), one of the most abundant membrane proteins of erythroblasts. A second transferrin receptor—TFR2—associates with the erythropoietin receptor and has been implicated in the regulation of erythropoiesis. In erythroblasts, both transferrin receptors adopt peculiarities such as an erythroid-specific regulation of TFR1 and a trafficking pathway reliant on TFR2 for iron. This review reports both trafficking and signaling functions of these receptors and reassesses the debated role of TFR2 in erythropoiesis in the light of recent findings. Potential therapeutic uses targeting the transferrin-TFR1 axis or TFR2 in hematological disorders are also discussed.

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“…166,167 Interestingly, not only the diferric form of transferrin has distinct signaling properties than the apotransferrin, but also two monomeric variants elicit differential effects. 168 Two mouse models with genetic disruption of iron binding to either N or C lobe are characterized with high serum NTBI levels, liver iron overload, and deficient hepcidin levels relative to liver iron status, with the last two parameters being more severely affected in mice with the N lobe blockage. The same model was also hallmarked by lower responsiveness to EPO, suggesting that N lobe occupancy has dominant roles in the regulation of erythropoiesis, likely through TFR2, the erythroid regulator of EPO-EPOR signaling.…”

Section: Iron-bound Transferrin As a Signaling Molecule Between Thementioning

confidence: 99%

Cell‐type‐specific insights into iron regulatory processes

Mleczko-Sanecka

Silvestri

2020

American J Hematol

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Despite its essential role in many biological processes, iron is toxic when in excess due to its propensity to generate reactive oxygen species. To prevent diseases associated with iron deficiency or iron loading, iron homeostasis must be tightly controlled. Intracellular iron content is regulated by the Iron Regulatory Element‐Iron Regulatory Protein (IRE‐IRP) system, whereas systemic iron availability is adjusted to body iron needs chiefly by the hepcidin‐ferroportin (FPN) axis. Here, we aimed to review advances in the field that shed light on cell‐type‐specific regulatory mechanisms that control or modify systemic and local iron balance, and how shifts in cellular iron levels may affect specialized cell functions.

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Lobe specificity of iron binding to transferrin modulates murine erythropoiesis and iron homeostasis

Abstract: In this Plenary Paper, the investigators demonstrate that the two monoferric forms of transferrin, the major plasma glycoprotein involved in cellular iron delivery, have functionally distinct effects on erythropoiesis and systemic iron regulation.

Cited by 38 publications

References 53 publications

Hepatic transferrin plays a role in systemic iron homeostasis and liver ferroptosis

Hepatic transferrin plays a role in systemic iron homeostasis and liver ferroptosis

Transferrin Receptors in Erythropoiesis

Cell‐type‐specific insights into iron regulatory processes

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