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The Hsc70 co-chaperone CHIP targets immature CFTR for proteasomal degradation

Abstract

The folding of both wild-type and mutant forms of the cystic-fibrosis transmembrane-conductance regulator (CFTR), a plasma-membrane chloride-ion channel, is inefficient1,2,3,4. Most nascent CFTR is retained in the endoplasmic reticulum and degraded by the ubiquitin proteasome pathway5,6,7. Aberrant folding and defective trafficking of CFTRΔF508 is the principal cause of cystic fibrosis3,8,9, but how the endoplasmic-reticulum quality-control system targets CFTR for degradation remains unknown. CHIP is a cytosolic U-box protein that interacts with Hsc70 through a set of tetratricorepeat motifs10. The U-box represents a modified form of the ring-finger motif that is found in ubiquitin ligases11 and that defines the E4 family of polyubiquitination factors12,13. Here we show that CHIP functions with Hsc70 to sense the folded state of CFTR and targets aberrant forms for proteasomal degradation by promoting their ubiquitination. The U-box appeared essential for this process because overexpresion of CHIPΔU-box inhibited the action of endogenous CHIP and blocked CFTR ubiquitination and degradation. CHIP is a co-chaperone that converts Hsc70 from a protein-folding machine into a degradation factor that functions in endoplasmic-reticulum quality control.

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Figure 1: The effect of CHIP expression on GFP–CFTR localization.
Figure 2: The influence of CHIP on CFTR biogenesis.
Figure 3: Complex formation between CHIP and CFTR.
Figure 4: The U-box is required for CHIP to promote CFTR ubiquitination.

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References

  1. Riordan, J. R. et al. Science 245, 1066–1073 (1989); erratum ibid. 245, 1437 (1989).

    Article  CAS  Google Scholar 

  2. Rich, D. P. et al. Nature 347, 358–363 (1990).

    Article  CAS  Google Scholar 

  3. Cheng, S. H et al. Cell. 63, 827–834 (1990).

    Article  CAS  Google Scholar 

  4. Ward, C. L. & Kopito, R. R. J. Biol. Chem. 269, 25710–25718 (1994).

    CAS  PubMed  Google Scholar 

  5. Lukacs, G. L. et al. EMBO J. 13, 6076–6086 (1994).

    Article  CAS  Google Scholar 

  6. Jensen, T. J. et al. Cell 83,129–135 (1995).

    Article  CAS  Google Scholar 

  7. Ward, C. L., Omura, S. & Kopito, R. R. Cell. 83, 121–127 (1995).

    Article  CAS  Google Scholar 

  8. Kartner, N. et al. Nature Genet. 1, 321–327 (1992).

    Article  CAS  Google Scholar 

  9. Welsh, M. J. & Smith, A. E. Cell 73, 1251–1254 (1993).

    Article  CAS  Google Scholar 

  10. Ballinger, C. A. et al. Mol. Cell. Biol. 19, 4535–4545 (1999).

    Article  CAS  Google Scholar 

  11. Aravind, L. & Koonin, E.V. Curr. Biol. 10, R132–R134 (2000).

    Article  CAS  Google Scholar 

  12. Pukatzki, S. et al. J. Biol. Chem. 273, 24131–24138 (1998).

    Article  CAS  Google Scholar 

  13. Koegl, M. et al. Cell 96, 635–644 (1999).

    Article  CAS  Google Scholar 

  14. Moyer, B.D. et al. J. Biol. Chem. 273, 21759–21768 (1998); erratum ibid. 273, 26256 (1998).

    Article  CAS  Google Scholar 

  15. Ward, C. L. & Kopito, R.R. J. Cell Biol. 143, 1883–1898 (1998).

    Article  Google Scholar 

  16. Wigley, W. C. et al. J. Cell Biol. 145, 481–490 (1999).

    Article  CAS  Google Scholar 

  17. Garcia-Mata, R. et al. J. Cell Biol. 146, 1239–1254 (1999).

    Article  CAS  Google Scholar 

  18. Strickland, E. et al. J. Cell Biol. 272, 25421–25424 (1997).

    CAS  Google Scholar 

  19. Meacham, G. C. et al. EMBO J. 18, 1492–1505 (1999).

    Article  CAS  Google Scholar 

  20. Pind, S., Riordan, J. R. & Williams, D. B. J. Biol. Chem. 269, 12784–12788 (1994).

    CAS  PubMed  Google Scholar 

  21. Loo, M. A. et al. EMBO J. 17, 6879–6887 (1998).

    Article  CAS  Google Scholar 

  22. Takayama, S. et al. EMBO J. 16, 4887–4896 (1997).

    Article  CAS  Google Scholar 

  23. Hohfeld, J. & Jentsch, S. EMBO J. 16, 6209–6216 (1997).

    Article  CAS  Google Scholar 

  24. Hohfeld, J., Minami, Y. & Hartl, F. U. Cell. 83, 589–598 (1995).

    Article  CAS  Google Scholar 

  25. Zhou, M. et al. J. Biol. Chem. 270, 25220–25224 (1995).

    Article  CAS  Google Scholar 

  26. Fisher, E. A. et al. J. Biol. Chem. 272, 20427–20434 (1997).

    Article  CAS  Google Scholar 

  27. Connell, P. et al. Nature Cell Biol. 3, 93–96

  28. Johnson, B. D. et al. J. Biol. Chem. 273, 3679–3686 (1998).

    Article  CAS  Google Scholar 

  29. Sommer, T. & Jentsch, S. Nature 365, 176–179 (1993).

    Article  CAS  Google Scholar 

  30. Hiller, M. M. et al. Science 273, 1725–1728 (1996).

    Article  CAS  Google Scholar 

  31. Lin, H & Wing, S. S. J. Biol. Chem. 274, 14685–146891 (1999).

    Article  CAS  Google Scholar 

  32. Katsanis, N. & Fisher, E. M. Genomics 51, 128–1231 (1998).

    Article  CAS  Google Scholar 

  33. Du, X. et al. J. Cell Biol. 141, 585–599 (1998).

    Article  CAS  Google Scholar 

  34. Wickner, S., Maurizi, M. R. & Gottesman, S. Science 286, 1888–1893 (1999).

    Article  CAS  Google Scholar 

  35. Kalin, N. et al. J. Clin. Invest. 103, 1379–1389 (1999).

    Article  CAS  Google Scholar 

  36. Odorizzi, C. G. et al. J. Cell Biol. 126, 317–330 (1994).

    Article  CAS  Google Scholar 

  37. Shamu, C. E. et al. J. Cell Biol. 147, 45–58 (1999).

    Article  CAS  Google Scholar 

  38. Cyr, D. M., Lu, X. & Douglas, M. G. J. Biol. Chem. 267, 20927–20931 (1992).

    CAS  PubMed  Google Scholar 

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Acknowledgements

We thank K. Kirk, D. Bewell and E. Stzul for providing antibodies; J. Collawn and H. Ginsberg for providing the transferrin receptor and apolipoprotein B48 expression plasmids; J. Höhfeld for helpful discussions and for providing Bag-1 and HIP expression plasmids; and B. Stanton for providing GFP–CFTR. D.M.C. is supported by grants from the NIH and the Cystic Fibrosis Foundation (CFF). C.P. is supported by the NIH. G.M. was supported by a predoctoral fellowship from the CFF.

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Correspondence to Douglas M. Cyr.

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Meacham, G., Patterson, C., Zhang, W. et al. The Hsc70 co-chaperone CHIP targets immature CFTR for proteasomal degradation. Nat Cell Biol 3, 100–105 (2001). https://doi.org/10.1038/35050509

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