Microbial Metabolite‐Stimulated Bitter Taste Receptor <scp>T2R14</scp> Signaling Is Modulated by <scp>CFTR</scp> Interactions

Bitter taste receptors (TAS2Rs or T2Rs) are a subset of G protein-coupled receptors (GPCRs) that play a key role in responding to microbial presence at epithelial surfaces. We previously reported that mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) affect innate immune signaling from the bitter taste receptor T2R14, but the mechanisms remain understudied. Here we employ multiple biophysical tools to investigate T2R14 and CFTR interactions and its effect on signaling. The data indicate that either the N-terminus or the NBD2/C-terminus of CFTR can independently interact with agonist-stimulated T2R14. The T2R14 agonist required for interaction with CFTR may be either a chemically synthesized bitter compound or a microbial metabolite. Agonist-bound T2R14 can engage both Gαi and Gαq subunits. Interplay between T2R14, its agonists, and the specific interacting CFTR domain governs the bias of signaling between Gi and Gq pathways. Taken together, the analysis of protein-protein interactions and signaling outcomes provides a possible explanation for the altered T2R signaling in CFTR mutant cells.