ABCMdb

PMID: 21148293

Grove DE, Fan CY, Ren HY, Cyr DM
The endoplasmic reticulum-associated Hsp40 DNAJB12 and Hsc70 cooperate to facilitate RMA1 E3-dependent degradation of nascent CFTRDeltaF508.
Mol Biol Cell. 2011 Feb 1;22(3):301-14. Epub 2010 Dec 9., 2011-02-01 [PubMed]

Sentences

No. Mutations Sentence Comment

14 ABCC7 p.Val510Asp Introduction of the V510D misfolding suppressor mutation into CFTRΔF508 modestly increased folding efficiency, whereas combined inactivation of JB12 and suppression of intrinsic folding defects permitted CFTRΔF508 to fold at 50% of wild-type efficiency. Login to comment 261 ABCC7 p.Val510Asp ABCC7 p.Val510Asp Folding of CFTRΔF508 increased dramatically upon introduction of the V510D suppressor mutation because CFTRΔF508 V510D accumulated at a C/B ratio of 0.2. Login to comment 262 ABCC7 p.Val510Asp Strikingly, depletion of JB12 increased the C/B ratio of CFTRΔF508 V510D more than eightfold to an impressive value near 1.6, which is 50% of the ratio observed for wild-type CFTR. Login to comment 263 ABCC7 p.Val510Asp In pulse-chase experiments, we also observed depletion of JB12 to permit CFTRΔF508 V510D to fold with ~50% of wild-type efficiency (Figure 8B). Login to comment 264 ABCC7 p.Val510Asp The combination of JB12 kd and Corr-4a treatment enabled CFTRΔF508 V510D to obtain a C/B ratio of 3.5, which is the same as the 3.4 value observed with wild-type CFTR. Login to comment 265 ABCC7 p.Val510Asp In pulse-chase experiments, we also observed that these conditions permit the B-form of CFTRΔF508 V510D to convert to the C-form with an efficiency that was greater than CFTR (Figure 8B). Login to comment 266 ABCC7 p.Val510Asp Corr-4a is able to stabilize transmembrane regions of CFTR (Wang et al., 2007; Grove et al., 2009), which may explain the twofold increase in CFTRΔF508 V510D folding efficiency that occurs when Corr-4a is present in JB12- depleted cells. Login to comment 277 ABCC7 p.Val510Asp We compared the extent to which the introduction of V510D, a misfolding suppressor mutation, into CFTRΔF508 versus inactivation of JB12 enhanced CFTRΔF508 folding (Figure 8). Login to comment 279 ABCC7 p.Val510Asp The folding of CFTR, CFTRΔF508, and CFTRΔF508 V510D was compared under control conditions, upon JB12 depletion, when cells were treated with the folding corrector Corr-4a (Pedemonte et al., 2005), or with a combination of the above conditions. Login to comment 318 ABCC7 p.Val510Asp Transfections with JB12 siRNA oligos and pcDNA3.1(+)- CFTR, pcDNA3.1(+)-CFTRΔF508, or pcDNA3.1(+)-CFTRΔF508 V510D were performed as described in Materials and Methods. Login to comment