Activator of G protein Signaling‐3 (AGS3) regulates CXCR4 and CCR7 signaling in murine lymphocytes and bone marrow‐derived dendritic cells

Abstract

Activator of G‐protein Signaling 3 (AGS3), an accessory protein for G‐protein signaling, has functional roles in the kidney and CNS. Here we show that AGS3 is expressed in spleen, thymus and bone marrow‐derived dendritic cells (BMDCs), and is upregulated upon leukocyte activation. Using a recently developed bioluminescent resonance energy transfer (BRET) platform, we observed that AGS3 forms a chemokine regulated, Gαi‐dependent complex with CXCR4 and CCR7, suggesting that AGS3 may integrate signals from chemokine receptors. Indeed, Gαi2‐null mice exhibit altered lymphocyte differentiation, secretion and motility. We thus explored the role of AGS3 in immune cell function by characterizing chemokine receptor signaling in mice lacking AGS3. Although there were no differences in lymphocyte subsets, we observed defects in chemotaxis of AGS3‐null BMDCs, B‐ and T‐cells. This defect was not due to alterations in cell surface receptor expression, but may be explained by observed reductions in chemokine‐stimulated calcium release and altered Erk and Akt activation in AGS3‐null cells. These studies indicate a role for AGS3 in the regulation of G‐protein signaling in the immune system, providing unexpected venues for the potential development of therapeutic agents that modulate immune function by targeting these regulatory mechanisms.