Iron modulation of erythropoiesis is associated with Scribble-mediated control of the erythropoietin receptor

Shadi Khalil; Lorrie Delehanty; Stephen Grado; Maja Holy; Zollie White III; Katie Freeman; Ryo Kurita; Yukio Nakamura; Grant Bullock; Adam Goldfarb

doi:10.1084/jem.20170396

Back

Iron modulation of erythropoiesis is associated with Scribble-mediated control of the erythropoietin receptor

Journal article

Open access

Peer reviewed

Iron modulation of erythropoiesis is associated with Scribble-mediated control of the erythropoietin receptor

Shadi Khalil, Lorrie Delehanty, Stephen Grado, Maja Holy, Zollie White III, Katie Freeman, Ryo Kurita, Yukio Nakamura, Grant Bullock and Adam Goldfarb

The Journal of experimental medicine, Vol.215(2), pp.661-679

02/05/2018

DOI: 10.1084/jem.20170396

PMCID: PMC5789406

PMID: 29282252

Files and links (1)

url

https://doi.org/10.1084/jem.20170396View

Published (Version of record) Open Access

Abstract

Iron-restricted human anemias are associated with the acquisition of marrow resistance to the hematopoietic cytokine erythropoietin (Epo). Regulation of Epo responsiveness by iron availability serves as the basis for intravenous iron therapy in anemias of chronic disease. Epo engagement of its receptor normally promotes survival, proliferation, and differentiation of erythroid progenitors. However, Epo resistance caused by iron restriction selectively impairs proliferation and differentiation while preserving viability. Our results reveal that iron restriction limits surface display of Epo receptor in primary progenitors and that mice with enforced surface retention of the receptor fail to develop anemia with iron deprivation. A mechanistic pathway is identified in which erythroid iron restriction down-regulates a receptor control element, Scribble, through the mediation of the iron-sensing transferrin receptor 2. Scribble deficiency reduces surface expression of Epo receptor but selectively retains survival signaling via Akt. This mechanism integrates nutrient sensing with receptor function to permit modulation of progenitor expansion without compromising survival.

Animals

Cathepsins - metabolism

Cell Line

Erythroid Precursor Cells - metabolism

Erythroid Precursor Cells - ultrastructure

Erythropoiesis - drug effects

Humans

Intracellular Signaling Peptides and Proteins - metabolism

Iron - pharmacology

Isocitrates - pharmacology

Membrane Proteins - metabolism

Mice, Inbred C57BL

Models, Biological

Protein Stability - drug effects

Receptors, Erythropoietin - metabolism

Receptors, Transferrin - metabolism

Tumor Suppressor Proteins - metabolism

Details

Title: Subtitle: Iron modulation of erythropoiesis is associated with Scribble-mediated control of the erythropoietin receptor
Creators: Shadi Khalil - University of Virginia
Lorrie Delehanty - University of Virginia
Stephen Grado - University of Virginia
Maja Holy - University of Virginia
Zollie White III - University of Virginia
Katie Freeman - University of Virginia
Ryo Kurita - RIKEN BioResource Research Center
Yukio Nakamura - RIKEN BioResource Research Center
Grant Bullock - University of Pittsburgh Medical Center
Adam Goldfarb - University of Virginia
Resource Type: Journal article
Publication Details: The Journal of experimental medicine, Vol.215(2), pp.661-679
DOI: 10.1084/jem.20170396
PMID: 29282252
PMCID: PMC5789406
NLM abbreviation: J Exp Med
ISSN: 0022-1007
eISSN: 1540-9538
Grant note: R01 DK101550 / NIDDK NIH HHS P30 CA044579 / NCI NIH HHS R01 DK079924 / NIDDK NIH HHS T32 CA009109 / NCI NIH HHS K08 HL093355 / NHLBI NIH HHS T32 GM007267 / NIGMS NIH HHS
Language: English
Date published: 02/05/2018
Academic Unit: Pathology
Record Identifier: 9984697642702771

Metrics

8 Record Views

59 Times Cited - Web of Science