한빛사논문
Ok-Hee Kim1, Geun-Hyung Kang1, June Hur1, Jinwook Lee1, YunJae Jung2, In-Sun Hong3, Hookeun Lee4, Seung-Yong Seo4, Dae Ho Lee5, Cheol Soon Lee6, In-Kyu Lee7, Susan Bonner-Weir8, Jongsoon Lee9, Young Joo Park10, Hyeonjin Kim11, Steven E. Shoelson8,* and Byung-Chul Oh1,*
1Department of Physiology, Lee Gil Ya Cancer and Diabetes Institute, Gachon University College of Medicine, Incheon 21999, Republic of Korea. 2Department of Microbiology, Lee Gil Ya Cancer and Diabetes Institute, Gachon University College of Medicine, Incheon 21999, Republic of Korea. 3Department of Molecular Medicine, Lee Gil Ya Cancer and Diabetes Institute, Gachon University College of Medicine, Incheon 21999, Republic of Korea. 4College of Pharmacy, Gachon University, Incheon 21936, Republic of Korea. 5Department of Internal Medicine, Gachon University Gil Medical Center, Incheon 21565, Republic of Korea. 6Medical Health Research Center, Korea University College of Medicine, Seoul 02841, Republic of Korea. 7Department of Biomedical Science, Graduate School of Medicine, Kyungpook National University, Daegu 41404, Republic of Korea. 8Joslin Diabetes Center and Department of Medicine, Harvard Medical School, One Joslin Place, Boston, MA 02215, USA. 9Soonchunhyang Institute of Medi-bio Science (SIMS), Cheonan-si 31151, Republic of Korea. 10Department of Internal Medicine, Seoul National University Hosptial, Seoul 03080, Republic of Korea. 11Department of Radiology, Seoul National University College of Medicine, Seoul 03080, Republic of Korea.
*Correspondence and requests for materials should be addressed to Steven E. Shoelson or Byung-Chul Oh.
Abstract
Apoptotic cells are rapidly engulfed and removed by phagocytes after displaying cell surface eat-me signals. Among many phospholipids, only phosphatidylserine (PS) is known to act as an eat-me signal on apoptotic cells. Using unbiased proteomics, we identified externalized phosphatidylinositides (PIPs) as apoptotic eat-me signals recognized by CD14+ phagocytes. Exofacial PIPs on the surfaces of early and late-apoptotic cells were observed in patches and blebs using anti-PI(3,4,5)P3 antibody, AKT- and PLCδ PH-domains, and CD14 protein. Phagocytosis of apoptotic cells was blocked either by masking exofacial PIPs or by CD14 knockout in phagocytes. We further confirmed that exofacial PIP+ thymocytes increased dramatically after in vivo irradiation and that exofacial PIP+ cells represented more significant populations in tissues of Cd14−/− than WT mice, especially after induction of apoptosis. Our findings reveal exofacial PIPs to be previously unknown cell death signals recognized by CD14+ phagocytes.
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