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

Catriona Kelly, Mark T. Williams, Kathryn Mitchell, J. Stuart Elborn, Madeleine Ennis, Bettina C. Schock

Research output: Contribution to journalArticle

Abstract

A20 is a lipopolysaccharide (LPS)-inducible, cytoplasmic zinc finger protein, which inhibits Toll-like receptor-activated nuclear factor (NF)-¿B 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-¿B 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-¿B-driven inflammation.
Original languageEnglish
Pages (from-to)1315-1323
Number of pages9
JournalEuropean Respiratory Journal
Volume41
Issue number6
DOIs
Publication statusPublished - 1 Jun 2013

Keywords

  • cystic fibrosis
  • A20 protein
  • epithelial cells
  • nuclear factor -¿B
  • pharmacy

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