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Identification d'une nouvelle voie de dégradation dépendante du GTP dans le réticulum endoplasmique : cas de la protéine mutée CFTR-F508del

Abstract : F508del -CFTR, the most frequent mutation found in patients with cystic fibrosis (CF), was among the first misfolded membrane proteins for which a role of ubiquitin and proteasome in ERAD was described. However, proteasome-mediated ERAD of membrane proteins is a challenging process because substrate and degradation machinery are located in different cellular compartments. Luminal domains and transmembrane segments of membrane proteins not only need to be unfolded, but should also undergo retrograde translocation and/or extraction from lipid bilayer in order to reach proteolytic sites within the 20S particle. However in the absence of ATP and in the presence of protéasome inhibitors, the degradation of F508del -CFTR is only modestly inhibited, suggesting that other proteolytic system may contribute to the degradation of the mutant CFTR. To date, no other proteases or proteolytic systems have been demonstrated to contribute to the F508del -CFTR elimination. Our present study represents the initial attempt to characterize the proteasome-independent proteolytic pathway of F508del -CFTR.
For the first time, we point out the role of GTP and heterotrimeric G proteins in the disposal of the mutant CFTR. Through our results, we demonstrate that this proteolytic pathway is restricted to RE. In parallel, we also investigated the role of protéasome and ATP in the degradation of F508del -CFTR and showed the absence of correlation between proteasomal activity and the elimination of the mutant CFTR. All together our results suggest that the ER-GTP dependent degradation pathway may be a complementary system that contributes to the disposal of ER-misfolded membrane proteins.
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https://tel.archives-ouvertes.fr/tel-00178339
Contributor : Béatrice de Keukeleire <>
Submitted on : Wednesday, October 10, 2007 - 5:27:25 PM
Last modification on : Wednesday, November 4, 2020 - 2:23:25 PM
Long-term archiving on: : Sunday, April 11, 2010 - 10:43:41 PM

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  • HAL Id : tel-00178339, version 1

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Béatrice de Keukeleire. Identification d'une nouvelle voie de dégradation dépendante du GTP dans le réticulum endoplasmique : cas de la protéine mutée CFTR-F508del. Biologie cellulaire. Université Joseph-Fourier - Grenoble I, 2007. Français. ⟨tel-00178339⟩

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