AdaSGC binds Hsc70s to inhibit ATPase activity. Using single-turnover assays, adaSGC, a soluble SGC mimic, preferentially inhibited Hsp40-activated Hsc70 ATP hydrolysis (Ki ∼ 10 μM) to reduce C-terminal Hsc70-peptide binding and, potentially, chaperone function. ERAD of misfolded ΔF508 CFTR requires Hsc70-Hsp40 chaperones. In transfected baby hamster kidney (BHK) cells, adaSGC increased ΔF508CFTR ERAD escape, and after low-temperature glycerol rescue, maturation, and iodide efflux. Inhibition of SGC biosynthesis reduced ΔF508CFTR but not wtCFTR expression, whereas depletion of other glycosphingolipids had no affect. WtCFTR transfected BHK cells showed increased SGC synthesis compared with ΔF508CFTR/mock-transfected cells. Partial rescue of ΔF508CFTR by low-temperature glycerol increased SGC synthesis. AdaSGC also increased cellular endogenous SGC levels. SGC in the lung, liver, and kidney was severely depleted in ΔF508CFTR compared with wtCFTR mice, suggesting a role for CFTR in SGC biosynthesis. © 2009 Elsevier Ltd. All rights reserved.
Park, H. J., Mylvaganum, M., McPherson, A., Fewell, S. W., Brodsky, J. L., & Lingwood, C. A. (2009). A Soluble Sulfogalactosyl Ceramide Mimic Promotes ΔF508 CFTR Escape from Endoplasmic Reticulum Associated Degradation. Chemistry and Biology, 16(4), 461–470. https://doi.org/10.1016/j.chembiol.2009.02.014