title: Caspase-mediated cleavage of phospholipid flippase for apoptotic phosphatidylserine exposure.
abstract: Phospholipids are asymmetrically distributed in the plasma membrane. This asymmetrical distribution is disrupted during apoptosis, exposing phosphatidylserine (PtdSer) on the cell surface. Using a haploid genetic screen in human cells, we found that ATP11C (adenosine triphosphatase type 11C) and CDC50A (cell division cycle protein 50A) are required for aminophospholipid translocation from the outer to the inner plasma membrane leaflet; that is, they display flippase activity. ATP11C contained caspase recognition sites, and mutations at these sites generated caspase-resistant ATP11C without affecting its flippase activity. Cells expressing caspase-resistant ATP11C did not expose PtdSer during apoptosis and were not engulfed by macrophages, which suggests that inactivation of the flippase activity is required for apoptotic PtdSer exposure. CDC50A-deficient cells displayed PtdSer on their surface and were engulfed by macrophages, indicating that PtdSer is sufficient as an "eat me" signal.
authors.affiliation: Department of Medical Chemistry, Graduate School of Medicine, Kyoto University, Yoshida-Konoe, Kyoto 606-8501, Japan.
authors.forename: Katsumori
authors.initials: K
authors.lastname: Segawa
authors.affiliation: Department of Medical Chemistry, Graduate School of Medicine, Kyoto University, Yoshida-Konoe, Kyoto 606-8501, Japan.
authors.forename: Sachiko
authors.initials: S
authors.lastname: Kurata
authors.affiliation: Department of Medical Chemistry, Graduate School of Medicine, Kyoto University, Yoshida-Konoe, Kyoto 606-8501, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Yanagihashi
authors.affiliation: Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, Netherlands.
authors.forename: Thijn R
authors.initials: TR
authors.lastname: Brummelkamp
authors.affiliation: Center for Genomic Medicine, Graduate School of Medicine, Kyoto University, Yoshida-Konoe, Kyoto 606-8501, Japan.
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Matsuda
authors.affiliation: Department of Medical Chemistry, Graduate School of Medicine, Kyoto University, Yoshida-Konoe, Kyoto 606-8501, Japan. Core Research for Evolutional Science and Technology, Japan Science and Technology Corporation, Kyoto 606-8501, Japan. snagata@mfour.med.kyoto-u.ac.jp.
authors.forename: Shigekazu
authors.initials: S
authors.lastname: Nagata
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism*; D002460:Cell Line; D002462:Cell Membrane / Q000201:enzymology*; D005820:Genetic Testing; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D026901:Membrane Transport Proteins; D010718:Phosphatidylserines / Q000378:metabolism*; D049294:Phospholipid Transfer Proteins / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport
chemical_list: D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D010718:Phosphatidylserines; D049294:Phospholipid Transfer Proteins; C526978:TMEM30a protein, human; D020169:Caspases; C000588974:ATP11C protein, human; D000251:Adenosine Triphosphatases