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RETRACTED ARTICLE: Binding to the transferrin receptor is required for endocytosis of HFE and regulation of iron homeostasis

Nature Cell Biology volume 2, pages 953–957 (2000)Cite this article

A Retraction to this article was published on 01 July 2003

This article has been updated

Abstract

HFE, the protein that is mutated in hereditary haemochromatosis, binds to the transferrin receptor (TfR). Here we show that wild-type HFE and TfR localize in endosomes and at the basolateral membrane of a polarized duodenal epithelial cell line, whereas the primary haemochromatosis HFE mutant, and another mutant with impaired TfR-binding ability accumulate in the ER/Golgi and at the basolateral membrane, respectively. Levels of the iron-storage protein ferritin are greatly reduced and those of TfR are slightly increased in cells expressing wild-type HFE, but not in cells expressing either mutant. Addition of an endosomal-targeting sequence derived from the human low-density lipoprotein receptor (LDLR) to the TfR-binding-impaired mutant restores its endosomal localization but not ferritin reduction or TfR elevation. Thus, binding to TfR is required for transport of HFE to endosomes and regulation of intracellular iron homeostasis, but not for basolateral surface expression of HFE.

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Figure 1: Confocal images of TfR and HFE–GFP distributions in untransfected and HFE-transfected HuTu-80 cells.
Figure 2: Confocal images of the distributions of HFE, transferrin and calnexin in HFE-transfected HuTu-80 cells.
Figure 3: Expression of ferritin and TfR in untransfected and HFE-transfected HuTu-80 cells.
Figure 4: Confocal images of the distributions of TfR, HFE and transferrin in HuTu-80 cells expressing HFE–LDLR–GFP proteins.
Figure 5: Schematic diagrams of transport of wild-type and mutant HFE proteins in polarized epithelial cells.

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Change history

  • 01 July 2003

    In the course of repeating experiments described in the above paper, the authors have discovered that some of the confocal microscopy images presented in Figs 1 and 2 were inappropriately processed. The differences between the present confocal images and the ones published with the paper require us to revise the conclusion that TfR binding by HFE is required for endocytosis of HFE and HFE-mediated regulation of ferritin levels, and we are therefore retracting the paper.

References

  1. Cullen, L. M. et al. Annu. Rev. Med. 50, 87– 98 (1999).

    Article  CAS  Google Scholar 

  2. Feder, J. N. et al. Nature Genet. 13, 399– 408 (1996).

    Article  CAS  Google Scholar 

  3. Lebrón, J. A. et al. Cell 93, 111–123 (1998).

    Article  Google Scholar 

  4. Parkkila, S. et al. Proc. Natl Acad. Sci. USA 94, 13198 –13202 (1997).

    Article  CAS  Google Scholar 

  5. Feder, J. N. et al. Proc. Natl Acad. Sci. USA 95, 1472– 1477 (1998).

    Article  CAS  Google Scholar 

  6. Richardson, D. R. & Ponka, P. Biochim. Biophys. Acta 1331, 1–40 ( 1997).

    Article  CAS  Google Scholar 

  7. Gross, C. N., Irrinki, A., Feder, J. N. & Enns, C. A. J. Biol. Chem. 273, 22068–22074 (1998).

    Article  CAS  Google Scholar 

  8. Riedel, H. D. et al. Blood 94, 3915–3921 (1999).

    CAS  PubMed  Google Scholar 

  9. Corsi, B. et al. FEBS Lett. 460, 149–152 (1999).

    Article  CAS  Google Scholar 

  10. Lebrón, J. A. & Bjorkman, P. J. J. Mol. Biol. 289, 1109–1118 ( 1999).

    Article  Google Scholar 

  11. Parkkila, S. et al. Proc. Natl Acad. Sci. USA 94, 2534– 2539 (1997).

    Article  CAS  Google Scholar 

  12. Waheed, A. et al. Proc. Natl Acad. Sci. USA 96, 1579– 1584 (1999).

    Article  CAS  Google Scholar 

  13. Feder, J. N. et al. J. Biol. Chem. 272, 14025– 14028 (1997).

    Article  CAS  Google Scholar 

  14. Waheed, A. et al. Proc. Natl Acad. Sci. USA 94, 12384 –12389 (1997).

    Article  CAS  Google Scholar 

  15. Bennett, M. J., Lebrón, J. A. & Bjorkman, P. J. Nature 403, 46–53 (2000).

    Article  CAS  Google Scholar 

  16. Roy, C. N., Penny, D. M., Feder, J. N. & Enns, C. A. J. Biol. Chem. 274, 9022–9028 (1999).

    Article  CAS  Google Scholar 

  17. Collawn, J. F. et al. EMBO J. 10, 3247–3253 (1991).

    Article  CAS  Google Scholar 

  18. Dunn, K. W., McGraw, T. E. & Maxfield, F. R. J. Cell Biol. 109, 3303– 3314 (1989).

    Article  CAS  Google Scholar 

  19. Heilker, R., Spiess, M. & Crottet, P. BioEssays 21, 558– 567 (1999).

    Article  CAS  Google Scholar 

  20. Hicke, L. & Riezman, H. Cell 84 , 277–287 (1996).

    Article  CAS  Google Scholar 

  21. Mukherjee, S., Ghosh, R. N. & Maxfield, F. R. Physiol. Rev. 77, 759–803 (1997).

    Article  CAS  Google Scholar 

  22. Mayor, S., Presley, J. F. & Maxfield, F. R. J. Cell Biol. 121, 1257– 1269 (1993).

    Article  CAS  Google Scholar 

  23. DeMaurex, N. et al. J. Biol. Chem. 273, 2044– 2051 (1998).

    Article  CAS  Google Scholar 

  24. Weisz, O. A., Machamer, C. E. & Hubbard, A. L. J. Biol. Chem. 267, 22282– 22288 (1992).

    CAS  PubMed  Google Scholar 

  25. Kain, S. R. in In Living Color: Protocols in Flow Cytometry and Cell Sorting (eds Diamond, R. A. & DeMaggio, S.) 199–226 (Springer, Heidelberg, 2000).

    Book  Google Scholar 

  26. Alvarez-Hernandez, X., Smith, M. & Glass, J. Blood 91, 3974– 3979 (1998).

    CAS  PubMed  Google Scholar 

  27. Williams, A. M. & Enns, C. A. J. Biol. Chem. 266, 17648–17654 ( 1991).

    CAS  PubMed  Google Scholar 

  28. Futter, C. E., Connolly, C. N., Cutler, D. F. & Hopkins, C. R. J. Biol. Chem. 270, 10999– 11003 (1995).

    Article  CAS  Google Scholar 

  29. Lebrón, J. A., West, A. P. & Bjorkman, P. J. J. Mol. Biol. 294, 239–245 (1999).

    Article  Google Scholar 

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Acknowledgements

We thank R. Diamond (Caltech Cell Sorting Facility) for assistance with flow cytometry, M. Bennett and M. Murphy for help with figures, W. L. Martin for the EGFP-Bluescript vector, D. Anderson for use of the confocal microscope, K. Zinn and L. Weiner for helpful discussions, and J. Feder and members of the Bjorkman laboratory for critical reading of the manuscript. This work was supported by the W. M. Keck Foundation Fund for Discovery in Basic Medical Research (to P.J.B.), the NIH (grant no. DK54488 to C.A.E.), and the Cancer Research Fund of the Damon Runyon-Walter Winchell Foundation (grant no. DRG-1445 to A.P.W.).

Author information

Author notes

  1. José A. Lebrón

    Present address: Merck and Co., 2 Sumneytown Pike, West Point, Pennsylvania, 19486, USA

  2. Jasvinder S. Nangiana

    Present address: Department of Molecular and Cellular Biology, University of California at Berkeley, Berkeley, California, 94720, USA

Authors and Affiliations

  1. Division of Biology 156-29, California Institute of Technology, Pasadena, 91125, California, USA

    T. S. Ramalingam, Anthony P. West Jr, José A. Lebrón, Jasvinder S. Nangiana, Thomas H. Hogan, Caroline A. Enns & Pamela J. Bjorkman

  2. Howard Hughes Medical Institute, California Institute of Technology, Pasadena, 91125, California, USA

    T. S. Ramalingam, Thomas H. Hogan & Pamela J. Bjorkman

  3. Department of Cell and Developmental Biology L-215 Oregon Health Sciences University, Portland, 97201, Oregon, USA

    Caroline A. Enns

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  1. T. S. Ramalingam
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Corresponding author

Correspondence to Pamela J. Bjorkman.

Supplementary information

Figure S1

Distributions of HFE-GFP, TfR and 5' nucleotidase in HuTu-80 cells transfected with wild-type HFE-GFP. Figure S2 Locations of the residues affected by the C260Y and W81A mutations. Figure S3 Distributions of TfR and HFE in HuTu-80 cells expressing HFE-LDLR-GFP proteins. (PDF 410 kb)

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Ramalingam, T., West, A., Lebrón, J. et al. RETRACTED ARTICLE: Binding to the transferrin receptor is required for endocytosis of HFE and regulation of iron homeostasis. Nat Cell Biol 2, 953–957 (2000). https://doi.org/10.1038/35046611

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  • DOI: https://doi.org/10.1038/35046611

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