title: Necrotic Cells Actively Attract Phagocytes through the Collaborative Action of Two Distinct PS-Exposure Mechanisms.
abstract: Necrosis, a kind of cell death closely associated with pathogenesis and genetic programs, is distinct from apoptosis in both morphology and mechanism. Like apoptotic cells, necrotic cells are swiftly removed from animal bodies to prevent harmful inflammatory and autoimmune responses. In the nematode Caenorhabditis elegans, gain-of-function mutations in certain ion channel subunits result in the excitotoxic necrosis of six touch neurons and their subsequent engulfment and degradation inside engulfing cells. How necrotic cells are recognized by engulfing cells is unclear. Phosphatidylserine (PS) is an important apoptotic-cell surface signal that attracts engulfing cells. Here we observed PS exposure on the surface of necrotic touch neurons. In addition, the phagocytic receptor CED-1 clusters around necrotic cells and promotes their engulfment. The extracellular domain of CED-1 associates with PS in vitro. We further identified a necrotic cell-specific function of CED-7, a member of the ATP-binding cassette (ABC) transporter family, in promoting PS exposure. In addition to CED-7, anoctamin homolog-1 (ANOH-1), the C. elegans homolog of the mammalian Ca(2+)-dependent phospholipid scramblase TMEM16F, plays an independent role in promoting PS exposure on necrotic cells. The combined activities from CED-7 and ANOH-1 ensure efficient exposure of PS on necrotic cells to attract their phagocytes. In addition, CED-8, the C. elegans homolog of mammalian Xk-related protein 8 also makes a contribution to necrotic cell-removal at the first larval stage. Our work indicates that cells killed by different mechanisms (necrosis or apoptosis) expose a common "eat me" signal to attract their phagocytic receptor(s); furthermore, unlike what was previously believed, necrotic cells actively present PS on their outer surfaces through at least two distinct molecular mechanisms rather than leaking out PS passively.
authors.affiliation: Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Zao
authors.initials: Z
authors.lastname: Li
authors.affiliation: Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Victor
authors.initials: V
authors.lastname: Venegas
authors.affiliation: the Graduate School of Natural Science and Technology, Kanazawa University, Shizenken, Kakuma-machi, Kanazawa, Ishikawa, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Nagaoka
authors.affiliation: the School of Pharmacy, Kanazawa University, Shizenken, Kakuma-machi, Kanazawa, Ishikawa, Japan.
authors.forename: Eri
authors.initials: E
authors.lastname: Morino
authors.affiliation: Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Prashant
authors.initials: P
authors.lastname: Raghavan
authors.affiliation: Department of Biomolecular Chemistry, University of Wisconsin-Madison, School of Medicine and Public Health, Madison, Wisconsin, United States of America.
authors.forename: Anjon
authors.initials: A
authors.lastname: Audhya
authors.affiliation: the Graduate School of Natural Science and Technology, Kanazawa University, Shizenken, Kakuma-machi, Kanazawa, Ishikawa, Japan; the School of Pharmacy, Kanazawa University, Shizenken, Kakuma-machi, Kanazawa, Ishikawa, Japan; the Graduate School of Medical Sciences, Kanazawa University, Shizenken, Kakuma-machi, Kanazawa, Ishikawa, Japan.
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Nakanishi
authors.affiliation: Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Zhou
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D017173:Caenorhabditis elegans / Q000276:immunology / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D009336:Necrosis; D010586:Phagocytes / Q000378:metabolism*; D010587:Phagocytosis; D010718:Phosphatidylserines / Q000378:metabolism*; D049294:Phospholipid Transfer Proteins / Q000378:metabolism
chemical_list: D018528:ATP-Binding Cassette Transporters; C112887:CED-7 protein, C elegans; C410597:CED-8 protein, C elegans; D029742:Caenorhabditis elegans Proteins; D008565:Membrane Proteins; D010718:Phosphatidylserines; D049294:Phospholipid Transfer Proteins; C422043:ced-1 protein, C elegans