Expression of the nuclear factor-κB inhibitor A20 is altered in the cystic fibrosis epithelium

Kelly, C., Williams, M. T., Mitchell, K., Elborn, J. S., Ennis, M. and Schock, B. C. (2012) Expression of the nuclear factor-κB inhibitor A20 is altered in the cystic fibrosis epithelium. European Respiratory Journal, 41(6), pp. 1315-1323. (doi: 10.1183/09031936.00032412) (PMID:23018911)

Abstract

A20 is a lipopolysaccharide (LPS)-inducible, cytoplasmic zinc finger protein, which inhibits Toll-like receptor-activated nuclear factor (NF)-κB signalling by deubiquitinating tumour necrosis factor receptor-associated factor (TRAF)-6. The action of A20 is facilitated by complex formation with ring finger protein (RNF)-11, Itch and TAX-1 binding protein-1 (TAX1BP1). This study investigated whether the expression of A20 is altered in the chronically inflamed cystic fibrosis (CF) airway epithelium. Nasal epithelial cells from CF patients (F508del homozygous), non-CF controls and immortalised epithelial cells (16HBE14o- and CFBE41o-) were stimulated with LPS. Cytoplasmic expression of A20 and expression of NF-κB subunits were analysed. Formation of the A20 ubiquitin editing complex was also investigated. In CFBE41o-, peak LPS-induced A20 expression was delayed compared with 16HBE14o- and fell significantly below basal levels 12–24 h after LPS stimulation. This was confirmed in primary CF airway cells. Additionally, a significant inverse relationship between A20 and p65 expression was observed. Inhibitor studies showed that A20 does not undergo proteasomal degradation in CFBE41o-. A20 interacted with TAX1BP1, RNF11 and TRAF6 in 16HBE14o- cells, but these interactions were not observed in CFBE41o-. The expression of A20 is significantly altered in CF, and important interactions with complex members and target proteins are lost, which may contribute to the state of chronic NF-κB-driven inflammation.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Williams, Dr Mark
• Authors: Kelly, C., Williams, M. T., Mitchell, K., Elborn, J. S., Ennis, M., and Schock, B. C.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: European Respiratory Journal
• Publisher: European Respiratory Society
• ISSN: 0903-1936
• ISSN (Online): 1399-3003