Pseudomonas aeruginosa reduces the expression of CFTR via post-translational modification of NHERF1

Rosa Rubino, Valentino Bezzerri, Maria Favia, Marcella Facchini, Maela Tebon, Anurag Kumar Singh, Brigitte Riederer, Ursula Seidler, Antonio Iannucci, Alessandra Bragonzi, Giulio Cabrini, Stephan J. Reshkin, Anna Tamanini

Research output: Contribution to journalArticle

Abstract

Pseudomonas aeruginosa infections of the airway cells decrease apical expression of both wild-type (wt) and F508del CFTR through the inhibition of apical endocytic recycling. CFTR endocytic recycling is known to be regulated by its interaction with PDZ domain containing proteins. Recent work has shown that the PDZ domain scaffolding protein NHERF1 finely regulates both wt and F508delCFTR membrane recycling. Here, we investigated the effect of P. aeruginosa infection on NHERF1 post-translational modifications and how this affects CFTR expression in bronchial epithelial cells and in murine lung. Both in vitro in bronchial cells, and in vivo in mice, infection reduced CFTR expression and increased NHERF1 molecular weight through its hyper-phosphorylation and ubquitination as a consequence of both bacterial pilin- and flagellin-mediated host–cell interaction. The ability of P. aeruginosa to down-regulate mature CFTR expression was reduced both in vivo in NHERF1 knockout mice and in vitro after silencing NHERF1 expression or mutations blocking its phosphorylation at serines 279 and 301. These studies provide the first evidence that NHERF1 phosphorylation may negatively regulate its action and, therefore, the assembly and function of multiprotein NHERF1 complexes in response to infection. The identification of molecular mechanisms responsible for these effects could identify novel targets to block potential P. aeruginosa interference with the efficacy of potentiator and/or corrector compounds.

Original languageEnglish
Pages (from-to)2269-2278
Number of pages10
JournalPflugers Archiv European Journal of Physiology
Volume466
Issue number12
DOIs
Publication statusPublished - Nov 18 2014

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Keywords

  • CFTR
  • Lung infection
  • NHERF1
  • Phosphorylation
  • Ubquitination

ASJC Scopus subject areas

  • Physiology
  • Clinical Biochemistry
  • Physiology (medical)
  • Medicine(all)

Cite this

Rubino, R., Bezzerri, V., Favia, M., Facchini, M., Tebon, M., Singh, A. K., Riederer, B., Seidler, U., Iannucci, A., Bragonzi, A., Cabrini, G., Reshkin, S. J., & Tamanini, A. (2014). Pseudomonas aeruginosa reduces the expression of CFTR via post-translational modification of NHERF1. Pflugers Archiv European Journal of Physiology, 466(12), 2269-2278. https://doi.org/10.1007/s00424-014-1474-6