Detection of folding defects in mutant CFTR by ERQC

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DESCRIPTION (provided by applicant): Cystic Fibrosis is a fatal lung disease caused by misfolding and premature proteasomal degradation of the mutant Cl- channel CFTRAF508. CFTRAF508 is synthesized in the endoplasmic reticulum (ER), but its folding arrests at an unknown intermediate step and it is selected for degradation prior to passage to the plasma membrane (PM). Loss of CFTR function leads to defects in the hydration of mucosal layers that line glands and airways and chronic infections that death occurs due to lung failure. Hope for the treatment of CF comes from observations that folding defects in CFTRAF508 are rescued by compounds that either alter the cellular folding environment. This competitive renewal application for 2RO1 GM56981 seeks to aid in the development of therapeutics to treat Cystic Fibrosis by elucidating defective steps in the CFTRAF508 folding pathway and identifying ER quality control (ERQC) factors that select CFTRAF508 for degradation. The three major objectives of the proposal are as follows 1. We seek to define the mechanism by which mutations in CFTR cause it to misfold and be degraded the ubiquitin proteasome system. 2. CFTR is a polytopic protein that exposes surfaces in the ER lumen, ER membrane, and cytosol. 'Thus, we will identify the components of the ERQC machinery that sense the folded state of different sub-domains in CFTR. Then, we will determine how the action of the ER localized and cytosolic QC factors is coordinated. 3. We propose to apply the knowledge obtained in our basic studies to develop approaches to block the selection of CFTRAF508 for premature degradation and promote its proper folding. Overall, our studies will provide basic information on protein QC that will aid in the development of therapeutics to treat CF.