SNX3 Regulates Recycling of the Transferrin Receptor and Iron Assimilation in Developing Erythrocytes*
Bibliographic record
Abstract
Abstract Abstract 607 Developing erythrocytes acquire large amounts of iron through the transferrin (Tf) cycle for heme synthesis. The Tf cycle involves unidirectional transport of transferrin-transferrin receptor 1 (Tf-TfR1) complexes from the plasma membrane to the early and recycling endosomes (Figure). Besides the requirement for the basic trafficking machinery, specific sorting molecules exist to ensure the efficient re-cycling of Tf-TfR1 complexes and targeted iron delivery. The trafficking of TfR1 from recycling endosomes to the cell surface was shown to be mediated by Sec15L1, an exocyst component, as its mutation causes anemia in the hemoglobin deficit (hbd) mouse. The sorting mechanisms responsible for earlier trafficking steps in intracellular transferrin cycle, however, are poorly understood. Here we report that sorting nexin 3 (SNX3), a cargo-specific retromer component, facilitates the endocytic recycling of TfR1, and thus, is required for the proper delivery of iron to erythroid progenitors for heme synthesis (Figure). Snx3 is highly expressed in hematopoietic tissues of zebrafish and mouse. Morpholino-mediated knockdown of snx3 in zebrafish embryos leads to a profound anemia. shRNA silencing of Snx3 in mouse primary fetal liver cells and mouse Friend erythroleukemia (MEL) cells inhibits the production of hemoglobin. We demonstrate that these defects are due to impaired transferrin-mediated iron uptake and delivery to the mitochondria. The impaired iron assimilation can be complemented with non-transferrin bound iron chelates, such as Fe-SIH (salicylaldehyde isonicotinoyl hydrazone). Furthermore, we show that SNX3 may act through direct physical interaction with TfR1 to sort Tf-TfR1 complexes to the recycling endosomes. Our data from genetic, biochemical, and chemical biological studies collectively show that SNX3 regulates TfR1 trafficking and iron homeostasis in developing erythrocytes. The identification of SNX3 as an essential co-regulatory protein that regulates Tf-mediated iron delivery for heme synthesis provides a new genetic tool for exploring human disorders of iron metabolism, such as the hypochromic anemias, and erythropoiesis. * Cell Metabolism (in revision). Disclosures: No relevant conflicts of interest to declare.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".