RT Journal Article
SR Electronic
T1 Chemoproteomics of microbiota metabolites reveals small-molecule agonists for orphan receptor GPRC5A
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.12.16.472979
DO 10.1101/2021.12.16.472979
A1 Xiaohui Zhao
A1 Kathryn R. Stein
A1 Victor Chen
A1 Matthew E. Griffin
A1 Howard C. Hang
YR 2021
UL http://biorxiv.org/content/early/2021/12/16/2021.12.16.472979.abstract
AB The microbiota generates diverse metabolites that can engage multiple pathways to modulate host physiology and disease, but their protein targets and mechanism(s) of action have not been fully elucidated. To address this challenge, we focused on indole-3-acetic acid (IAA), a prominent microbiota metabolite, and developed IAA-based chemical reporters for proteomic studies. We discovered that IAA interacts with many proteins in host cells, including small-molecule transporters, receptors and metabolic enzymes. Notably, our functional studies revealed that IAA binds to orphan G protein-coupled receptors such as GPRC5A, but only aromatic monoamines were capable of inducing GPRC5A signaling. Functional profiling of microbiota uncovered specific bacterial species and enzymes that generate GPRC5A agonists. Finally, biochemical characterization of GPRC5A activation identified more potent synthetic agonists as well as key amino acid residues involved in ligand binding. These studies highlight the utility of chemoproteomics to dissect protein targets and mechanisms of action for microbiota metabolites.Competing Interest StatementThe authors have declared no competing interest.