Snx3 regulates recycling of the transferrin receptor and iron assimilation

Caiyong Chen; Daniel Garcia-Santos; Yuichi Ishikawa; Alexandra Seguin; Liangtao Li; Katherine H. Fegan; Gordon J. Hildick-Smith; Dhvanit I. Shah; Jeffrey D. Cooney; Wen Chen; Matthew J. King; Yvette Y. Yien; Iman J. Schultz; Heidi Anderson; Arthur J. Dalton; Matthew L. Freedman; Paul D. Kingsley; James Palis; Shilpa M. Hattangadi; Harvey F. Lodish; Diane M. Ward; Jerry Kaplan; Takahiro Maeda; Prem Ponka; Barry H. Paw

doi:10.1016/j.cmet.2013.01.013

Snx3 regulates recycling of the transferrin receptor and iron assimilation

Caiyong Chen, Daniel Garcia-Santos, Yuichi Ishikawa, Alexandra Seguin, Liangtao Li, Katherine H. Fegan, Gordon J. Hildick-Smith, Dhvanit I. Shah, Jeffrey D. Cooney, Wen Chen, Matthew J. King, Yvette Y. Yien, Iman J. Schultz, Heidi Anderson, Arthur J. Dalton, Matthew L. Freedman, Paul D. Kingsley, James Palis, Shilpa M. Hattangadi, Harvey F. LodishDiane M. Ward, Jerry Kaplan, Takahiro Maeda, Prem Ponka, Barry H. Paw

Internal Medicine

Research output: Contribution to journal › Article

59 Citations (Scopus)

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.

Original language	English
Pages (from-to)	343-352
Number of pages	10
Journal	Cell metabolism
Volume	17
Issue number	3
DOIs	https://doi.org/10.1016/j.cmet.2013.01.013
Publication status	Published - Mar 5 2013

All Science Journal Classification (ASJC) codes

Physiology
Molecular Biology
Cell Biology

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Chen, C., Garcia-Santos, D., Ishikawa, Y., Seguin, A., Li, L., Fegan, K. H., Hildick-Smith, G. J., Shah, D. I., Cooney, J. D., Chen, W., King, M. J., Yien, Y. Y., Schultz, I. J., Anderson, H., Dalton, A. J., Freedman, M. L., Kingsley, P. D., Palis, J., Hattangadi, S. M., ... Paw, B. H. (2013). Snx3 regulates recycling of the transferrin receptor and iron assimilation. Cell metabolism, 17(3), 343-352. https://doi.org/10.1016/j.cmet.2013.01.013

Snx3 regulates recycling of the transferrin receptor and iron assimilation. / Chen, Caiyong; Garcia-Santos, Daniel; Ishikawa, Yuichi; Seguin, Alexandra; Li, Liangtao; Fegan, Katherine H.; Hildick-Smith, Gordon J.; Shah, Dhvanit I.; Cooney, Jeffrey D.; Chen, Wen; King, Matthew J.; Yien, Yvette Y.; Schultz, Iman J.; Anderson, Heidi; Dalton, Arthur J.; Freedman, Matthew L.; Kingsley, Paul D.; Palis, James; Hattangadi, Shilpa M.; Lodish, Harvey F.; Ward, Diane M.; Kaplan, Jerry; Maeda, Takahiro; Ponka, Prem; Paw, Barry H.

In: Cell metabolism, Vol. 17, No. 3, 05.03.2013, p. 343-352.

Research output: Contribution to journal › Article

Chen, C, Garcia-Santos, D, Ishikawa, Y, Seguin, A, Li, L, Fegan, KH, Hildick-Smith, GJ, Shah, DI, Cooney, JD, Chen, W, King, MJ, Yien, YY, Schultz, IJ, Anderson, H, Dalton, AJ, Freedman, ML, Kingsley, PD, Palis, J, Hattangadi, SM, Lodish, HF, Ward, DM, Kaplan, J, Maeda, T, Ponka, P & Paw, BH 2013, 'Snx3 regulates recycling of the transferrin receptor and iron assimilation', Cell metabolism, vol. 17, no. 3, pp. 343-352. https://doi.org/10.1016/j.cmet.2013.01.013

Chen, Caiyong ; Garcia-Santos, Daniel ; Ishikawa, Yuichi ; Seguin, Alexandra ; Li, Liangtao ; Fegan, Katherine H. ; Hildick-Smith, Gordon J. ; Shah, Dhvanit I. ; Cooney, Jeffrey D. ; Chen, Wen ; King, Matthew J. ; Yien, Yvette Y. ; Schultz, Iman J. ; Anderson, Heidi ; Dalton, Arthur J. ; Freedman, Matthew L. ; Kingsley, Paul D. ; Palis, James ; Hattangadi, Shilpa M. ; Lodish, Harvey F. ; Ward, Diane M. ; Kaplan, Jerry ; Maeda, Takahiro ; Ponka, Prem ; Paw, Barry H. / Snx3 regulates recycling of the transferrin receptor and iron assimilation. In: Cell metabolism. 2013 ; Vol. 17, No. 3. pp. 343-352.

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AU - Hildick-Smith, Gordon J.

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AU - Lodish, Harvey F.

AU - Ward, Diane M.

AU - Kaplan, Jerry

AU - Maeda, Takahiro

AU - Ponka, Prem

AU - Paw, Barry H.

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N2 - 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.

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