title: Pseudomonas aeruginosa Homoserine lactone activates store-operated cAMP and cystic fibrosis transmembrane regulator-dependent Cl- secretion by human airway epithelia.
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 Ca(2+) from the endoplasmic reticulum (ER), lowering [Ca(2+)] in the ER and thereby activating the Ca(2+)-sensitive ER signaling protein STIM1. 3O-C12 increases cytosolic [Ca(2+)] 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 Ca(2+) buffer that lowers [Ca(2+)] in the ER similar to the effect of 3O-C12 also increased cAMP and I(Cl). 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 [Ca(2+)] 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.
authors.affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, California 94720-3200, USA.
authors.forename: Christian
authors.initials: C
authors.lastname: Schwarzer
authors.forename: Steven
authors.initials: S
authors.lastname: Wong
authors.forename: James
authors.initials: J
authors.lastname: Shi
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Matthes
authors.forename: Beate
authors.initials: B
authors.lastname: Illek
authors.forename: Juan P
authors.initials: JP
authors.lastname: Ianowski
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Arant
authors.forename: Ehud
authors.initials: E
authors.lastname: Isacoff
authors.forename: Horia
authors.initials: H
authors.lastname: Vais
authors.forename: J Kevin
authors.initials: JK
authors.lastname: Foskett
authors.forename: Isabella
authors.initials: I
authors.lastname: Maiellaro
authors.forename: Aldebaran M
authors.initials: AM
authors.lastname: Hofer
authors.forename: Terry E
authors.initials: TE
authors.lastname: Machen
mesh_terms: D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000378:metabolism; D000838:Anions / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects / Q000235:genetics; D002461:Cell Line, Transformed; D002712:Chlorides / Q000378:metabolism*; D000242:Cyclic AMP / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D003550:Cystic Fibrosis / Q000235:genetics / Q000378:metabolism / Q000382:microbiology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D011552:Pseudomonas Infections / Q000235:genetics / Q000378:metabolism*; D011550:Pseudomonas aeruginosa / Q000378:metabolism*; D053038:Quorum Sensing / Q000187:drug effects; D020545:Respiratory Mucosa / Q000378:metabolism* / Q000382:microbiology; D000071737:Stromal Interaction Molecule 1
chemical_list: D000838:Anions; C505032:CFTR protein, human; D002712:Chlorides; D004791:Enzyme Inhibitors; D053496:Inositol 1,4,5-Trisphosphate Receptors; D008565:Membrane Proteins; D009363:Neoplasm Proteins; C103530:STIM1 protein, human; D000071737:Stromal Interaction Molecule 1; C088386:homoserine lactone; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D000242:Cyclic AMP; D015107:4-Butyrolactone; D002118:Calcium