Pseudomonas aeruginosaHomoserine Lactone Activates Store-operated cAMP and Cystic Fibrosis Transmembrane Regulator-dependent Cl−Secretion by Human Airway Epithelia

Schwarzer, Christian; Wong, Steven; Shi, James; Matthes, Elizabeth; Illek, Beate; Ianowski, Juan P.; Arant, Ryan J.; Isacoff, Ehud; Vais, Horia; Foskett, J. Kevin; Maiellaro, Isabella; Hofer, Aldebaran M.; Machen, Terry E.

Abstract

The ubiquitous bacterium Pseudomonas aeruginosa frequently causes hospital-acquired infections. P. aeruginosa also infects the lungs of cystic fibrosis (CF) patients and secretes N-(3-oxo-dodecanoyl)-S-homoserine lactone (3O-C12) to regulate bacterial gene expression critical for P. aeruginosa persistence. In addition to its effects as a quorum-sensing gene regulator in P. aeruginosa, 3O-C12 elicits cross-kingdom effects on host cell signaling leading to both pro- or anti-inflammatory effects. We find that in addition to these slow effects mediated through changes in gene expression, 3O-C12 also rapidly increases Cl− and fluid secretion in the cystic fibrosis transmembrane regulator (CFTR)-expressing airway epithelia. 3O-C12 does not stimulate Cl− secretion in CF cells, suggesting that lactone activates the CFTR. 3O-C12 also appears to directly activate the inositol trisphosphate receptor and release Ca2+ from the endoplasmic reticulum (ER), lowering [Ca2+] in the ER and thereby activating the Ca2+-sensitive ER signaling protein STIM1. 3O-C12 increases cytosolic [Ca2+] and, strikingly, also cytosolic [cAMP], the known activator of CFTR. Activation of Cl− current by 3O-C12 was inhibited by a cAMP antagonist and increased by a phosphodiesterase inhibitor. Finally, a Ca2+ buffer that lowers [Ca2+] in the ER similar to the effect of 3O-C12 also increased cAMP and ICl. The results suggest that 3O-C12 stimulates CFTR-dependent Cl− and fluid secretion in airway epithelial cells by activating the inositol trisphosphate receptor, thus lowering [Ca2+] in the ER and activating STIM1 and store-operated cAMP production. In CF airways, where CFTR is absent, the adaptive ability to rapidly flush the bacteria away is compromised because the lactone cannot affect Cl− and fluid secretion.

Citation

Schwarzer, C., Wong, S., Shi, J., Matthes, E., Illek, B., Ianowski, J. P., …Machen, T. E. (2010). Pseudomonas aeruginosaHomoserine Lactone Activates Store-operated cAMP and Cystic Fibrosis Transmembrane Regulator-dependent Cl−Secretion by Human Airway Epithelia. Journal of Biological Chemistry, 285(45), 34850-34863. https://doi.org/10.1074/jbc.m110.167668

• Journal Article Type: Article
• Acceptance Date: Nov 10, 2010
• Online Publication Date: Aug 25, 2010
• Publication Date: Nov 5, 2010
• Deposit Date: Apr 8, 2020
• Journal: Journal of Biological Chemistry
• Print ISSN: 0021-9258
• Electronic ISSN: 1083-351X
• Publisher: American Society for Biochemistry and Molecular Biology
• Peer Reviewed: Peer Reviewed
• Volume: 285
• Issue: 45
• Pages: 34850-34863
• DOI: https://doi.org/10.1074/jbc.m110.167668
• Public URL: https://nottingham-repository.worktribe.com/output/4237803
• Publisher URL: https://www.jbc.org/content/285/45/34850