Selection of misfolded CFTR for proteasomal degradation by sequential Quality Control checkpoints Public Deposited

Downloadable Content

Download PDF
Last Modified
  • March 21, 2019
Creator
  • Younger, J. Michael
    • Affiliation: School of Medicine, Department of Cell Biology and Physiology
Abstract
  • CFTR-delta-F508 exhibits a correctable protein-folding defect. Protein Quality Control components identify and degrade proteins such as CFTR-delta-F508 that fail to acquire a native conformation. Loss of CFTR activity results in improper lung mucosa hydration and causes cystic fibrosis. Components that function in the CFTR biogenic pathway have been identified. However, to more fully understand the folding defect and to identify the biogenic intermediate that is selected for degradation it is necessary to identify the Quality Control components responsible for CFTR-delta-F508 degradation. Herein we identify two novel multi-subunit E3 Ubiquitin Ligase complexes: the cytosolic Hsc70/CHIP/UbcH5a complex, and the ER localized Derlin-1/RMA1/Ubc6e complex. Inactivation of the Hsc70/CHIP/UbcH5a complex using a mutant dominant negative form of UbcH5a has led to the identification of a CFTR-delta-F508 biogenic intermediate that can acquire a detergent soluble stable interaction with molecular chaperones and upon exposure to 26 degrees C, can fold and be expressed at the plasma membrane (PM). Studies utilizing both the Hsc70/CHIP/UbcH5a complex and the Derlin-1/RMA1/Ubc6e complex to comparatively study the sensitivity of CFTR biogenic intermediates to each quality control component has led to the finding that the kinetically trapped folding intermediate caused by the delta-F508 mutation is identified by the Derlin-1/RMA1/Ubc6e complex early in the biogenic process. Thus, these studies have been instrumental in the discovery of two sequential Quality Control checkpoints that function to target CFTR-delta-F508 for proteasomal degradation.
Date of publication
DOI
Resource type
Rights statement
  • In Copyright
Advisor
  • Cyr, Douglas
Degree granting institution
  • University of North Carolina at Chapel Hill
Language
Access
  • Open access
Parents:

This work has no parents.

Items