Role of GRK in engulfment of apoptotic cells

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In the body, apoptotic cells are rapidly removed by the cells such as macrophages and dendritic cells. Otherwise, inefficient removal of apoptotic cells results in transition of apoptotic cells to late necrotic cells and leakage of their own intracellular contents. This leakage causes appearance of autoantibody and induction of inflammation, leading to collapse of the body’ s homeostasis. The removal of apoptotic cells is called as engulfment. So far, there are three engulfment pathways: Abl/Abi, ELMO/DOCK180, and ABC/MFGF10/GULF/dynamin signaling pathways. In this study, we revealed that G protein-coupled receptor (GPCR) kinase 6 (GRK6), which is believed to regulate GPCR function, was involved in engulfment. This pathway was independent of three known pathways. GRK6 bound Ezrin/Radixin/Moesin (ERM) and ultimately activated Rac1 that is indispensable for engulfment. GRK6-mediated engulfment was also observed in endogenous macrophages. In GRK6 knockout (GRK6-KO) mice, systemic lupus erythematosus (SLE), one of autoimmune diseases, -like symptoms such as increased anti-double strand DNA antibody in the plasma and deposition of immunocomplex in the kidney were observed. Furthermore, we observed abnormalities in the spleen. In white pulp of the spleen that removes apoptotic B cells, the number of ungulfed apoptotic cells in GRK6-KO mice was higher than that in wild type mice. In red pulp of the spleen that removes aged red blood cells, we observed the increased iron deposition due to impaired removal of aged red blood cells. These results suggest that GRK6 is a mediator of engulf apoptotic cells, and impaired function of GRK6 results in autoimmune disease and affects recycling of red blood cells. This study reveals that GRK has a new role in the cells andbody, although GRK is generally accepted as a mediator of GPCR regulation.