title: GRK6 deficiency in mice causes autoimmune disease due to impaired apoptotic cell clearance.
abstract: Efficient engulfment of apoptotic cells is critical for maintaining tissue homoeostasis. When phagocytes recognize 'eat me' signals presented on the surface of apoptotic cells, this subsequently induces cytoskeletal rearrangement of phagocytes for the engulfment through Rac1 activation. However, the intracellular signalling cascades that result in Rac1 activation remain largely unknown. Here we show that G-protein-coupled receptor kinase 6 (GRK6) is involved in apoptotic cell clearance. GRK6 cooperates with GIT1 to activate Rac1, which promotes apoptotic engulfment independently from the two known DOCK180/ELMO/Rac1 and GULP1/Rac1 engulfment pathways. As a consequence, GRK6-deficient mice develop an autoimmune disease. GRK6-deficient mice also have increased iron stores in splenic red pulp in which F4/80(+) macrophages are responsible for senescent red blood cell clearance. Our results reveal previously unrecognized roles for GRK6 in regulating apoptotic engulfment and its fundamental importance in immune and iron homoeostasis.
authors: Department of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors: Michio
authors: M
authors: Nakaya
authors: Mitsuru
authors: M
authors: Tajima
authors: Hidetaka
authors: H
authors: Kosako
authors: Takeo
authors: T
authors: Nakaya
authors: Akiko
authors: A
authors: Hashimoto
authors: Kenji
authors: K
authors: Watari
authors: Hiroaki
authors: H
authors: Nishihara
authors: Mina
authors: M
authors: Ohba
authors: Shiori
authors: S
authors: Komiya
authors: Naoki
authors: N
authors: Tani
authors: Motohiro
authors: M
authors: Nishida
authors: Hisaaki
authors: H
authors: Taniguchi
authors: Yoji
authors: Y
authors: Sato
authors: Mitsuru
authors: M
authors: Matsumoto
authors: Makoto
authors: M
authors: Tsuda
authors: Masahiko
authors: M
authors: Kuroda
authors: Kazuhide
authors: K
authors: Inoue
authors: Hitoshi
authors: H
authors: Kurose
mesh_terms: D000818:Animals; D017209:Apoptosis; D001327:Autoimmune Diseases / Q000097:blood / Q000201:enzymology* / Q000473:pathology*; D018797:Cell Cycle Proteins / Q000378:metabolism; D016922:Cellular Senescence; D003598:Cytoskeletal Proteins / Q000378:metabolism; D015180:Electrophoresis, Gel, Two-Dimensional; D004912:Erythrocytes / Q000378:metabolism / Q000473:pathology; D005260:Female; D054768:G-Protein-Coupled Receptor Kinases / Q000172:deficiency* / Q000378:metabolism; D020690:GTPase-Activating Proteins / Q000378:metabolism; D006801:Humans; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008840:Microfilament Proteins / Q000378:metabolism; D041681:NIH 3T3 Cells; D010587:Phagocytosis; D010766:Phosphorylation; D015398:Signal Transduction; D013154:Spleen / Q000378:metabolism / Q000473:pathology; D020744:rac GTP-Binding Proteins / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D003598:Cytoskeletal Proteins; D020690:GTPase-Activating Proteins; C120766:Git1 protein, mouse; D008565:Membrane Proteins; D008840:Microfilament Proteins; C071058:moesin; C071776:radixin; D054768:G-Protein-Coupled Receptor Kinases; C089176:G-protein-coupled receptor kinase 6; D020744:rac GTP-Binding Proteins