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Vol. 20, Issue 18, 4059-4069, September 15, 2009

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Mechanisms for Rescue of Correctable Folding Defects in CFTRF508

Diane E. Grove^*, Meredith F.N. Rosser^*, Hong Yu Ren^*, Anjaparavanda P. Naren, and Douglas M. Cyr^*

*Department of Cell and Developmental Biology and the UNC-Cystic Fibrosis Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599; and Department of Physiology, University of Tennessee Health Science Center, Memphis, TN 38163

Submitted September 19, 2008; Revised June 30, 2009; Accepted July 14, 2009
Monitoring Editor: Reid Gilmore

Premature degradation of CFTRF508 causes cystic fibrosis (CF). CFTRF508 folding defects are conditional and folding correctors are being developed as CF therapeutics. How the cellular environment impacts CFTRF508 folding efficiency and the identity of CFTRF508's correctable folding defects is unclear. We report that inactivation of the RMA1 or CHIP ubiquitin ligase permits a pool of CFTRF508 to escape the endoplasmic reticulum. Combined RMA1 or CHIP inactivation and Corr-4a treatment enhanced CFTRF508 folding to 3–7-fold greater levels than those elicited by Corr-4a. Some, but not all, folding defects in CFTRF508 are correctable. CHIP and RMA1 recognize different regions of CFTR and a large pool of nascent CFTRF508 is ubiquitinated by RMA1 before Corr-4a action. RMA1 recognizes defects in CFTRF508 related to misassembly of a complex that contains MSD1, NBD1, and the R-domain. Corr-4a acts on CFTRF508 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 CFTRF508 folding and provide a therapeutic approach for CF.

Address correspondence to: Douglas M. Cyr (DMCYR{at}med.unc.edu).

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