Mechanisms for Rescue of Correctable Folding Defects in CFTRΔF508

Premature degradation of CFTR Delta F508 causes cystic fibrosis (CF). CFTR Delta F508 folding defects are conditional and folding correctors are being developed as CF therapeutics. How the cellular environment impacts CFTR Delta F508 folding efficiency and the identity of CFTR Delta F508's correctable folding defects is unclear. We report that inactivation of the RMA1 or CHIP ubiquitin ligase permits a pool of CFTR Delta F508 to escape the endoplasmic reticulum. Combined RMA1 or CHIP inactivation and Corr-4a treatment enhanced CFTR Delta F508 folding to 3-7-fold greater levels than those elicited by Corr-4a. Some, but not all, folding defects in CFTR Delta F508 are correctable. CHIP and RMA1 recognize different regions of CFTR and a large pool of nascent CFTR Delta F508 is ubiquitinated by RMA1 before Corr-4a action. RMA1 recognizes defects in CFTR Delta F508 related to misassembly of a complex that contains MSD1, NBD1, and the R-domain. Corr-4a acts on CFTR Delta F508 after MSD2 synthesis and was ineffective at rescue of Delta 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 Delta F508 folding and provide a therapeutic approach for CF.