GRK6 deficiency in mice causes autoimmune disease due to impaired apoptotic cell clearance

Michio Nakaya, Mitsuru Tajima, Hidetaka Kosako, Takeo Nakaya, Akiko Hashimoto, Kenji Watari, Hiroaki Nishihara, Mina Ohba, Shiori Komiya, Naoki Tani, Motohiro Nishida, Hisaaki Taniguchi, Yoji Sato, Mitsuru Matsumoto, Makoto Tsuda, Masahiko Kuroda, Kazuhide Inoue and Hitoshi Kurose ()
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Michio Nakaya: Graduate School of Pharmaceutical Sciences, Kyushu University
Mitsuru Tajima: Graduate School of Pharmaceutical Sciences, Kyushu University
Hidetaka Kosako: Institute for Enzyme Research, University of Tokushima
Takeo Nakaya: Tokyo Medical University
Akiko Hashimoto: Graduate School of Pharmaceutical Sciences, Kyushu University
Kenji Watari: Graduate School of Pharmaceutical Sciences, Kyushu University
Hiroaki Nishihara: Graduate School of Pharmaceutical Sciences, Kyushu University
Mina Ohba: Graduate School of Pharmaceutical Sciences, Kyushu University
Shiori Komiya: Graduate School of Pharmaceutical Sciences, Kyushu University
Naoki Tani: Institute for Enzyme Research, University of Tokushima
Motohiro Nishida: Graduate School of Pharmaceutical Sciences, Kyushu University
Hisaaki Taniguchi: Institute for Enzyme Research, University of Tokushima
Yoji Sato: National Institute of Health Sciences, Setagaya, Tokyo 158-8501, Japan
Mitsuru Matsumoto: Institute for Enzyme Research, University of Tokushima
Makoto Tsuda: Molecular and System Pharmacology, Graduate School of Pharmaceutical Sciences, Kyushu University
Masahiko Kuroda: Tokyo Medical University
Kazuhide Inoue: Molecular and System Pharmacology, Graduate School of Pharmaceutical Sciences, Kyushu University
Hitoshi Kurose: Graduate School of Pharmaceutical Sciences, Kyushu University

Nature Communications, 2013, vol. 4, issue 1, 1-11

Abstract: 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.

Date: 2013
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DOI: 10.1038/ncomms2540

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