Abstract
Regulation of the Erythroid Iron Deprivation Response By a TfR2-Scribble-Epor Integrated Module Coupling Iron Sensing with Receptor Presentation
Blood, Vol.128(22), pp.3615-3615
12/02/2016
DOI: 10.1182/blood.V128.22.3615.3615
Abstract
Abstract
Iron deficiency in humans causes desensitization of erythroid progenitors to erythropoietin, the principal cytokine for erythroid survival, proliferation, and differentiation. This nutrient deprivation response acts in a lineage-selective, non-apoptotic manner to restrain expansion of the tissue responsible for the majority of iron consumption, thereby triaging iron utilization under conditions of deficiency. The molecular basis for this response is incompletely understood but involves transferrin receptor 2 (TfR2) and aconitase enzymatic activity as extra- and intracellular iron sensors. Here, we identify a multi-component, integrated module connecting these two elements of erythroid iron sensing with endo-lysosomal trafficking, receptor surface delivery, and configuration of EpoR signaling. Specifically, iron and aconitase activity modulate the rate of TfR2 catabolism by cathepsin protease activity. Scribble, a conserved regulator of receptor transport and signaling, binds TfR2 and serves as a downstream effector through to its co-catabolism. Scribble levels in turn influence surface delivery of the erythropoietin receptor (EpoR), which physically interacts with both Scribble and TfR2. The TfR2-dependent downregulation of Scribble associated with iron deprivation diminishes surface EpoR density and skews its signaling from JAK-STAT to Akt pathways. Mice with surface-trapped, endocytosis-defective EpoR fail to develop anemia in response to iron deficiency. These findings establish a tissue-specific nutrient sensing pathway relevant to the pathogenesis of human anemias and their resistance to erythropoietin therapy.
Disclosures
No relevant conflicts of interest to declare.
Details
- Title: Subtitle
- Regulation of the Erythroid Iron Deprivation Response By a TfR2-Scribble-Epor Integrated Module Coupling Iron Sensing with Receptor Presentation
- Creators
- Shadi Khalil - University of VirginiaLorrie L Delehanty - University of VirginiaMaja Holy - University of VirginiaStephen Grado - University of VirginiaGrant C. Bullock - University of VirginiaAdam Goldfarb - University of Virginia
- Resource Type
- Abstract
- Publication Details
- Blood, Vol.128(22), pp.3615-3615
- Publisher
- AMER SOC HEMATOLOGY; WASHINGTON
- DOI
- 10.1182/blood.V128.22.3615.3615
- ISSN
- 0006-4971
- eISSN
- 1528-0020
- Number of pages
- 1
- Language
- English
- Date published
- 12/02/2016
- Academic Unit
- Pathology
- Record Identifier
- 9984700255402771
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