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