Mechanisms for Rescue of Correctable Folding Defects in CFTR F508

Premature degradation of CFTR F508 causes cystic fibrosis (CF). CFTR F508 folding defects are conditional and folding correctors are being developed as CF therapeutics. How the cellular environment impacts CFTR F508 folding efficiency and the identity of CFTR F508’s correctable folding defects is unclear. We report that inactivation of the RMA1 or CHIP ubiquitin ligase permits a pool of CFTR F508 to escape the endoplasmic reticulum. Combined RMA1 or CHIP inactivation and Corr-4a treatment enhanced CFTR F508 folding to 3–7-fold greater levels than those elicited by Corr-4a. Some, but not all, folding defects in CFTR F508 are correctable. CHIP and RMA1 recognize different regions of CFTR and a large pool of nascent CFTR F508 is ubiquitinated by RMA1 before Corr-4a action. RMA1 recognizes defects in CFTR F508 related to misassembly of a complex that contains MSD1, NBD1, and the R-domain. Corr-4a acts on CFTR F508 after MSD2 synthesis and was ineffective at rescue of F508 dependent folding defects in amino-terminal regions. In contrast, misfolding caused by the rare CF-causing mutation V232D in MSD1 was highly correctable by Corr-4a. Overall, correction of folding defects recognized by RMA1 and/or global modulation of ER quality control has the potential to increase CFTR F508 folding and provide a therapeutic approach for CF.