Expression of the nuclear factor-κB 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

9 Citations (Scopus)

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.
LanguageEnglish
Pages1315-1323
Number of pages9
JournalEuropean Respiratory Journal
Volume41
Issue number6
Early online date27 Sep 2012
DOIs
Publication statusPublished - 1 Jun 2013

Fingerprint

Cystic Fibrosis
Lipopolysaccharides
Epithelium
Carrier Proteins
Epithelial Cells
TNF Receptor-Associated Factor 6
Tumor Necrosis Factor Receptor-Associated Peptides and Proteins
Proteins
Toll-Like Receptors
Zinc Fingers
Ubiquitin
Nose
Cell Communication
Fingers
Fibrosis
Inflammation

Keywords

  • cystic fibrosis
  • A20 protein
  • epithelial cells
  • nuclear factor -κB
  • pharmacy

Cite this

Kelly, C., Williams, M. T., Mitchell, K., Elborn, J. S., Ennis, M., & Schock, B. C. (2013). Expression of the nuclear factor-κB inhibitor A20 is altered in the cystic fibrosis epithelium. European Respiratory Journal, 41(6), 1315-1323. https://doi.org/10.1183/09031936.00032412
Kelly, Catriona ; Williams, Mark T. ; Mitchell, Kathryn ; Elborn, J. Stuart ; Ennis, Madeleine ; Schock, Bettina C. / Expression of the nuclear factor-κB inhibitor A20 is altered in the cystic fibrosis epithelium. In: European Respiratory Journal. 2013 ; Vol. 41, No. 6. pp. 1315-1323.
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Kelly, C, Williams, MT, Mitchell, K, Elborn, JS, Ennis, M & Schock, BC 2013, 'Expression of the nuclear factor-κB inhibitor A20 is altered in the cystic fibrosis epithelium' European Respiratory Journal, vol. 41, no. 6, pp. 1315-1323. https://doi.org/10.1183/09031936.00032412

Expression of the nuclear factor-κB inhibitor A20 is altered in the cystic fibrosis epithelium. / Kelly, Catriona; Williams, Mark T.; Mitchell, Kathryn; Elborn, J. Stuart; Ennis, Madeleine; Schock, Bettina C.

In: European Respiratory Journal, Vol. 41, No. 6, 01.06.2013, p. 1315-1323.

Research output: Contribution to journalArticle

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T1 - Expression of the nuclear factor-κB inhibitor A20 is altered in the cystic fibrosis epithelium

AU - Kelly, Catriona

AU - Williams, Mark T.

AU - Mitchell, Kathryn

AU - Elborn, J. Stuart

AU - Ennis, Madeleine

AU - Schock, Bettina C.

PY - 2013/6/1

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N2 - 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.

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KW - A20 protein

KW - epithelial cells

KW - nuclear factor -κB

KW - pharmacy

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