SUMMARY 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.

Eukaryotic cell glycosphingolipids (GSLs) are central components of membrane lipid microdomains that function as trans plasmamembrane signaling foci. GSLs serve as important receptors and coreceptors, primarily to mediate host/microbial pathogen interactions, and undergo unique intracellular trafficking pathways. As such, their chemical modification can generate interventive therapeutic strategies and biologic probes. The process of achieving such goals via chemistry of the carbohydrate is in its infancy, but substitution within the lipid moiety has been used extensively. A consideration of the importance of the lipid moiety in GSL function has led to novel chemical approaches that attempt to retain this property.