The CFTR (cystic fibrosis transmembrane conductance regulator) gene, defective in cystic fibrosis, codes for a polytopic apical membrane protein functioning as a chloride channel. Wild-type (wt) CFTR matures inefficiently and CFTR with a deletion of Phe-508 (F508del), the most frequent mutation, is substantially retained as a core-glycosylated intermediate in the endoplasmic reticulum (ER), probably due to misfolding that is recognized by the cellular quality control machinery involving molecular chaperones. Here, we overexpressed the heat-shock protein (Hsp) 70 chaperone in vivo and observed no changes in degradation rate of the core-glycosylated form, nor in the efficiency of its conversion into the fully glycosylated form, for either wt- or F508del-CFTR, contrary to previous in vitro studies on the affect of heat-shock cognate (Hsc) 70 on part of the first nucleotide-binding domain of CFTR. Co-transfection of Hsp70 with its co-chaperone human DnaJ homologue (Hdj)-1/Hsp40, however, stabilizes the immature form of wt-CFTR, but not of F508del-CFTR, suggesting that these chaperones act on a wt-specific conformation. As the efficiency of conversion into the fully glycosylated form is not increased under Hsp70/Hdj-1 overexpression, the lack of these two chaperones does not seem to be critical for CFTR maturation and ER retention. The effects of 4-phenylbutyrate and deoxyspergualin, described previously to interfere with Hsp70 binding, were also tested upon CFTR degradation and processing. The sole effect observed was destabilization of F508del-CFTR.
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September 2002
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Research Article|
September 15 2002
The human DnaJ homologue (Hdj)-1/heat-shock protein (Hsp) 40 co-chaperone is required for the in vivo stabilization of the cystic fibrosis transmembrane conductance regulator by Hsp70
Carlos M. FARINHA;
Carlos M. FARINHA
∗Centro de Genética Humana, Instituto Nacional de Saúde Dr. Ricardo Jorge, Av. Padre Cruz, 1649-016 Lisboa, Portugal
†Departamento de Química e Bioquímica, Faculdade de Ciências da Universidade de Lisboa, 1749-016 Lisboa, Portugal,
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Paulo NOGUEIRA;
Paulo NOGUEIRA
‡Observatório Nacional de Saúde, Instituto Nacional de Saúde Dr. Ricardo Jorge, 1649-016 Lisboa, Portugal
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Filipa MENDES;
Filipa MENDES
∗Centro de Genética Humana, Instituto Nacional de Saúde Dr. Ricardo Jorge, Av. Padre Cruz, 1649-016 Lisboa, Portugal
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Deborah PENQUE;
Deborah PENQUE
∗Centro de Genética Humana, Instituto Nacional de Saúde Dr. Ricardo Jorge, Av. Padre Cruz, 1649-016 Lisboa, Portugal
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Margarida D. AMARAL
Margarida D. AMARAL
1
∗Centro de Genética Humana, Instituto Nacional de Saúde Dr. Ricardo Jorge, Av. Padre Cruz, 1649-016 Lisboa, Portugal
†Departamento de Química e Bioquímica, Faculdade de Ciências da Universidade de Lisboa, 1749-016 Lisboa, Portugal,
1To whom correspondence should be addressed, at the Centro de Genética Humana (e-mail mdamaral@igc.gulbenkian.pt).
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Publisher: Portland Press Ltd
Received:
November 22 2001
Revision Received:
June 10 2002
Accepted:
June 17 2002
Accepted Manuscript online:
June 17 2002
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London ©2002
2002
Biochem J (2002) 366 (3): 797–806.
Article history
Received:
November 22 2001
Revision Received:
June 10 2002
Accepted:
June 17 2002
Accepted Manuscript online:
June 17 2002
Citation
Carlos M. FARINHA, Paulo NOGUEIRA, Filipa MENDES, Deborah PENQUE, Margarida D. AMARAL; The human DnaJ homologue (Hdj)-1/heat-shock protein (Hsp) 40 co-chaperone is required for the in vivo stabilization of the cystic fibrosis transmembrane conductance regulator by Hsp70. Biochem J 15 September 2002; 366 (3): 797–806. doi: https://doi.org/10.1042/bj20011717
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