Pseudomonas aeruginosa 3-oxo-C12HSL-induced apoptosis involves bitter taste receptor T2R14 and the mitochondrial calcium uniporter.

Pseudomonas aeruginosa is an opportunistic pathogen that infects immunocompromised patients. P. aeruginosa infects airways in cystic fibrosis (CF) and chronic rhinosinusitis (CRS) and also infects oral and nasal epithelia in immunocompromised head and neck squamous cell carcinoma patients. P. aeruginosa produces several apoptosis-inducing factors, including N-3-oxo-dodecanoyl-L-homoserine lactone (3-oxo-C12HSL). Additionally, 3-oxo-C12HSL activates several human bitter taste G protein-coupled receptors (taste family 2 receptors, or T2Rs), including T2R14 expressed throughout the body. We previously discovered that activation of T2R14 causes apoptosis in either HNSCC cells or primary nasal cells cultured to reflect a squamous phenotype. While the conducting airways are normally a pseudostratified columnar epithelium, epithelial de-differentiation, squamous metaplasia, and enhanced apoptosis occur in both CF and CRS airways, often correlating with sites of P. aeruginosa colonization. We hypothesized that 3-oxo-C12HSL-induced apoptosis may involve T2R14. We found that 3-oxo-C12HSL activates sustained intracellular Ca2+ responses originating from ER Ca2+ stores consistent with a G protein-coupled receptor pathway. 3-oxo-C12HSL responses were inhibited with T2R14 antagonists and T2R14 shRNA. T2R14 activation led to sustained mitochondrial Ca2+ elevations that were blocked by inhibitors of the mitochondrial calcium uniporter (MCU). As observed with other T2R14 agonists, 3-oxo-C12HSL inhibited cell viability through mitochondrial depolarization, Ca2+-dependent mitochondrial ROS production, and apoptosis. T2R14 activation by 3-oxo-C12HSL likely induces MCU-mediated mitochondrial Ca2+ overload. Because T2R14 and MCU are druggable targets that appear to play important roles in P. aeruginosa 3-oxo-C12HSL-induced apoptosis, we hypothesize that pharmacological inhibition of T2R14 or MCU might protect against host epithelial damage during P. aeruginosa infections.