Mutation-Induced Functional Alterations of CCR6.

Area of Science:

• Immunology
• Molecular Pharmacology
• Genetics

Background:

• C-C chemokine receptor 6 (CCR6) is crucial in modulating inflammation.
• Genetic links exist between CCR6 polymorphisms and immune disorders like rheumatoid arthritis and Crohn's disease.
• Pharmacological effects of natural CCR6 missense mutations remain largely uncharacterized.

Purpose of the Study:

• To characterize the functional impact of naturally occurring CCR6 missense mutations.
• To investigate G protein and β-arrestin signaling pathways affected by CCR6 variants.
• To explore the potential of engineered CCR6 variants with altered signaling.

Main Methods:

• Assessed G protein-mediated signaling for wild-type (WT) and mutant CCR6 receptors.
• Utilized bioluminescence resonance energy transfer (BRET) assay to measure β-arrestin recruitment.
• Engineered constitutively active CCR6 receptors to study gain-of-function effects.

Main Results:

• WT CCR6 displayed ligand-independent G protein activity.
• Five common CCR6 missense variants showed reduced basal and/or ligand-induced Gαi protein signaling (loss-of-function).
• Engineered CCR6 mutants demonstrated enhanced basal G protein signaling; one mutant (T98P) showed elevated β-arrestin recruitment.

Conclusions:

• Point mutations in CCR6 can lead to either loss-of-function or gain-of-function phenotypes.
• Naturally occurring CCR6 variants differentially affect G protein and β-arrestin signaling.
• Further research is needed to understand how CCR6 variants influence immune cell function and human diseases.