Abstract
Introduction: A20 is a negative regulator of TLR driven NF-uB signalling. This regulatory function is reliant on the formation of a ubiquitin editing complex comprising A20, Ring Finger protein (RNF)11, Itch (E3 ligase) and the adaptor protein TAX1BP1 [1]. In CF epithelial cells LPS reduces the expression of all complex members. Moreover, A20 does not interact with other complex members or target proteins [2,3]. Here we sought to determine the role of CFTR in the down-regulation of A20 ubiquitin editing genes. Methods: 16HBE41obronchial epithelial cells were transfected with CFTR siRNA. Primary nasal epithelial cells (NECs) from CF patients [F508del homozygous (n = 6), or R117H/F508del heterozygous (n = 5)] and age-matched controls (n = 6) were fully differentiated at air-liquid interface and treated with LPS (P. aeruginosa, Sigma) for 24h. A20, RNF11, Itch and TAX1BP1 mRNA expression was assessed by qPCR and analysed by ANOVA. Results: Following CFTR knockdown (transfection efficiency 72%±5.34%, n = 3) A20 mRNA was reduced by 43% (P < 0.01). This would indicate that A20 expression may be regulated by CFTR. In line with this, expression of A20, RNF11, Itch and TAX1BP1 was significantly reduced (P < 0.01–0.001) in NECs from both CF groups compared with controls. Moreover, the reduction in A20, RNF11 and TAX1BP1 (P < 0.05) expression was more pronounced in the F508del than R117H group. Conclusion: Expression of the A20 ubiquitin editing complex reflects CF disease severity and may prove a novel predictor of inflammation. The CF Trust UK (PJ541) supported this work
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