Macrophages express numerous G protein-coupled receptors (GPCRs) that regulate adhesion, migration, and activation, but the function of orphan receptor GPRC5B in macrophages is unknown. Both resident Show more
Macrophages express numerous G protein-coupled receptors (GPCRs) that regulate adhesion, migration, and activation, but the function of orphan receptor GPRC5B in macrophages is unknown. Both resident peritoneal and bone marrow-derived macrophages from myeloid-specific GPRC5B-deficient mice show increased migration and phagocytosis, resulting in improved bacterial clearance in a peritonitis model. In other models such as myocardial infarction, increased myeloid cell recruitment has adverse effects. Mechanistically, we found that GPRC5B physically interacts with GPCRs of the prostanoid receptor family, resulting in enhanced signaling through the prostaglandin E receptor 2 (EP2). In GPRC5B-deficient macrophages, EP2-mediated anti-inflammatory effects are diminished, resulting in hyperactivity. Using in silico modelling and docking, we identify residues potentially mediating GPRC5B/EP2 dimerization and show that their mutation results in loss of GPRC5B-mediated facilitation of EP2 signaling. Finally, we demonstrate that decoy peptides mimicking the interacting sequence are able to reduce GPRC5B-mediated facilitation of EP2-induced cAMP signaling in macrophages. Show less
The locus of the human proprotein convertase subtilisin-kexin type-7 (PC7) gene (PCSK7) is on chromosome 11q23.3 close to the gene cluster APOA5/APOA4/APOC3/APOA1, a region implicated in the regulatio Show more
The locus of the human proprotein convertase subtilisin-kexin type-7 (PC7) gene (PCSK7) is on chromosome 11q23.3 close to the gene cluster APOA5/APOA4/APOC3/APOA1, a region implicated in the regulation of lipoprotein metabolism. A GWAS reported the association of PCSK7 SNPs with plasma triglyceride (TG), and exome sequencing of African Americans revealed the association of a low-frequency coding variant of PC7 (R504H; SNP rs142953140) with a ~ 30% TG reduction. Another PCSK7 SNP rs508487 is in linkage disequilibrium with a promoter variant of the liver-derived apolipoprotein A-V (apoA-V), an indirect activator of the lipoprotein lipase (LpL), and is associated with elevated TG levels. We thus hypothesized that PC7 regulates the levels/activity of apoA-V. Studies in the human hepatic cell line HuH7 revealed that wild-type (WT) PC7 and its endoplasmic reticulum (ER)-retained forms bind to and enhance the degradation of human apoA-V in acidic lysosomes in a nonenzymatic fashion. PC7-induced degradation of apoA-V is inhibited by bafilomycin A1 and the alkalinizing agents: chloroquine and NH Show less