@article{593cbc5f239f468ca339eb3798a9309f,
title = "Snx3 regulates recycling of the transferrin receptor and iron assimilation",
abstract = "Sorting of endocytic ligands and receptors is critical for diverse cellular processes. The physiological significance of endosomal sorting proteins in vertebrates, however, remains largely unknown. Here we report that sorting nexin 3 (Snx3) facilitates the recycling of transferrin receptor (Tfrc) and thus is required for the proper delivery of iron to erythroid progenitors. Snx3 is highly expressed in vertebrate hematopoietic tissues. Silencing of Snx3 results in anemia and hemoglobin defects in vertebrates due to impaired transferrin (Tf)-mediated iron uptake and its accumulation in early endosomes. This impaired iron assimilation can be complemented with non-Tf iron chelates. We show that Snx3 and Vps35, a component of the retromer, interact with Tfrc to sort it to the recycling endosomes. Our findings uncover a role of Snx3 in regulating Tfrc recycling, iron homeostasis, and erythropoiesis. Thus, the identification of Snx3 provides a genetic tool for exploring erythropoiesis and disorders of iron metabolism.",
author = "Caiyong Chen and Daniel Garcia-Santos and Yuichi Ishikawa and Alexandra Seguin and Liangtao Li and Fegan, {Katherine H.} and Hildick-Smith, {Gordon J.} and Shah, {Dhvanit I.} and Cooney, {Jeffrey D.} and Wen Chen and King, {Matthew J.} and Yien, {Yvette Y.} and Schultz, {Iman J.} and Heidi Anderson and Dalton, {Arthur J.} and Freedman, {Matthew L.} and Kingsley, {Paul D.} and James Palis and Hattangadi, {Shilpa M.} and Lodish, {Harvey F.} and Ward, {Diane M.} and Jerry Kaplan and Takahiro Maeda and Prem Ponka and Paw, {Barry H.}",
note = "Funding Information: We thank members of our lab (Jacky Chung, Diana Branco, Adrianne Kolpak) and Dr. Elizabeth Leibold for critical discussion and reading of the manuscript, Dr. Yan Zhang for help with the enzymatic assays, Dr. Rebecca Wingert for the zebrafish tfr1a cDNA clone, Dr. Leonard Zon for the Tg(globin LCR:eGFP) transgenic line, Dr. Karin Hoffmeister for use of the FACS machine, and Christian Lawrence and his team for the zebrafish husbandry. This work was supported by grants from the Cooley{\textquoteright}s Anemia Foundation (C.C., D.I.S.), the American Heart Association (J.D.C., M.J.K., A.J.D.), the American Society of Hematology (M.J.K.), the Dutch National Science Fund-NWO (I.J.S.), the Finnish Sigrid Juselius Foundation (H.A.), the March of Dimes Foundation (6-FY09-289, B.H.P.), the Canadian Institutes of Health Research (D.G.-S. and P.P.), and the National Institutes of Health (T32 HL007574, Y.Y.Y.; K01 DK085217, D.I.S.; K08 DK076848, S.M.H.; R01 DK09361, J.P.; P01 HL032262, H.F.L.; R01 HL026922, D.M.W.; R01 DK052380, J.K.; R01 DK070838 and P01 HL032262, B.H.P.). C.C. and B.H.P. designed studies, performed experiments, analyzed data, and wrote the manuscript. D.G.-S. and P.P. measured the uptake of 59 Fe-Tf. Y.I. and T.M. measured the surface-bound Tfrc level and the recycling of internalized Tf-Alexa 647. A.S., L.L., D.M.W., and J.K. analyzed the subcellular localization of Tf-Alexa 488 and performed the enzymatic assays. K.H.F., P.D.K., and J.P. performed the in situ hybridization studies in mouse embryos. G.J.H.-S. and J.D.C. performed flow cytometry experiments on Tg(globin-LCR:eGFP) line. D.I.S. performed the qRT-PCR analysis. W.C. constructed Tfrc-FLAG and Abcb10-FLAG constructs and generated the MEL clones stably expressing these constructs. M.J.K., Y.Y.Y., I.J.S., H.A., and A.J.D. helped with RNA-seq data analysis and zebrafish colony maintenance. M.L.F. analyzed the GWAS database for potential interesting SNPs in Snx3 . S.M.H. and H.F.L. provided gene expression data from the RNA-seq experiment and knocked down Snx3 in mouse primary fetal liver cells. ",
year = "2013",
month = mar,
day = "5",
doi = "10.1016/j.cmet.2013.01.013",
language = "English",
volume = "17",
pages = "343--352",
journal = "Cell Metabolism",
issn = "1550-4131",
publisher = "Cell Press",
number = "3",
}