Caohuy H, Yang Q, Eudy Y, Ha TA, Xu AE, Glover M, Frizzell RA, Jozwik C, Pollard HB

Cystic Fibrosis (CF) is due to a folding defect in the CFTR protein. The most common mutation [ΔF508] prevents CFTR from trafficking to the apical plasma membrane. Here we show that activation of the PDK1/SGK1 signaling pathway with C4-Ceramide (C4-CER), a non-toxic small molecule, functionally corrects the trafficking defect in ...

Read More

both cultured CF cells and primary epithelial cell explants from CF patients. The mechanism of C4-CER action involves a series of mutual autophosphorylation and phosphorylation events between PDK1 and SGK1. Detailed mechanistic studies indicate that C4-CER initially induces autophosphorylation of SGK1 at Ser422. SGK1[pS422] and C4-CER co-incidently bind PDK1 and permit PDK1 to autophosphorylate at Ser241. Then, PDK1 [pS241] phosphorylates SGK1[pS422] at Thr256 to generate fully activated SGK1 [pS422, pT256]. SGK1[pS422, pT256] then phosphorylates and inactivates the E3 ubiquitin ligase Nedd4-2. [ΔF508]CFTR is thus free to traffick to the plasma membrane. Importantly, C4-CER-mediated activation of both PDK1 and SGK1 is independent of the PI3K/Akt/mTOR signaling pathway. Physiologically, C4-CER significantly increases maturation and stability of [ΔF508]CFTR (t1/2 ≈ 10 h); enhances cAMP-activated chloride secretion; and suppresses hypersecretion of Interleukin-8 (IL-8). We suggest that therapies for CF directed against the PDK1/SGK1 signaling pathway, such as that provided by C4-CER, is a novel therapeutic strategy for a life-limiting disorder which affects one child, on average, each day.

Date: Nov. 10, 2014

View in: Pubmed Google Scholar

169993