Neutrophils play essential anti-microbial and inflammatory roles in host defense, however their activities are tightly regulated as neutrophil dysfunction often leads to detrimental inflammatory and autoimmune diseases. Here, we identified a novel PR3/CD177/GPR97/PAR2/CD16b interactome as a critical modulator of neutrophil activation. Using multiple approaches, we deorphanized GPR97, a human neutrophil-restricted adhesion G protein-coupled receptor (aGPCR), as the interacting protein and allosteric activator of CD177-associated membrane proteinase 3 (mPR3). Structural and deletion analysis of the GPR97 extracellular region disclosed two independent mPR3-binding domains. The efficient binding and activation of mPR3 by GPR97 required a macromolecular CD177/GPR97/PAR2/CD16b interactome and resulted in the transactivation of PAR2, another GPCR. GPR97-mediated PAR2 transactivation in neutrophils elicited strong inflammatory activation, triggering anti-microbial activities and endothelial dysfunction. Altogether, we identify a novel aGPCR-GPCR transactivation mechanism that directs neutrophil activation and inflammation. The PR3/CD177/GPR97/PAR2/CD16b interactome represents a potential therapeutic target for neutrophil-mediated inflammatory diseases.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.