title: ESCRT-III Acts Downstream of MLKL to Regulate Necroptotic Cell Death and Its Consequences.
abstract: The activation of mixed lineage kinase-like (MLKL) by receptor-interacting protein kinase-3 (RIPK3) results in plasma membrane (PM) disruption and a form of regulated necrosis, called necroptosis. Here, we show that, during necroptosis, MLKL-dependent calcium (Ca2+) influx and phosphatidylserine (PS) exposure on the outer leaflet of the plasma membrane preceded loss of PM integrity. Activation of MLKL results in the generation of broken, PM "bubbles" with exposed PS that are released from the surface of the otherwise intact cell. The ESCRT-III machinery is required for formation of these bubbles and acts to sustain survival of the cell when MLKL activation is limited or reversed. Under conditions of necroptotic cell death, ESCRT-III controls the duration of plasma membrane integrity. As a consequence of the action of ESCRT-III, cells undergoing necroptosis can express chemokines and other regulatory molecules and promote antigenic cross-priming of CD8+T cells.
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Yi-Nan
authors.initials: YN
authors.lastname: Gong
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Cliff
authors.initials: C
authors.lastname: Guy
authors.affiliation: Division of Renal Medicine, Clinical Sciences, Intervention and Technology, Karolinska Institutet, 171 76 Stockholm, Sweden.
authors.forename: Hannes
authors.initials: H
authors.lastname: Olauson
authors.affiliation: Institute of Pathology, University Hospital of Cologne, 50674 Cologne, Germany.
authors.forename: Jan Ulrich
authors.initials: JU
authors.lastname: Becker
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Mao
authors.initials: M
authors.lastname: Yang
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Fitzgerald
authors.affiliation: Division of Nephrology, Department of Internal Medicine III, University Hospital Carl Gustav Carus at the Technische Universität Dresden, 01307 Dresden, Germany. Electronic address: andreas.linkermann@ukdd.de.
authors.forename: Andreas
authors.initials: A
authors.lastname: Linkermann
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. Electronic address: douglas.green@stjude.org.
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Green
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism*; D002470:Cell Survival; D056827:Endosomal Sorting Complexes Required for Transport / Q000378:metabolism*; D019073:HT29 Cells; D006801:Humans; D019169:Jurkat Cells; D051379:Mice; D041681:NIH 3T3 Cells; D009336:Necrosis / Q000378:metabolism*; D010718:Phosphatidylserines; D011494:Protein Kinases / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D056827:Endosomal Sorting Complexes Required for Transport; D010718:Phosphatidylserines; C570693:MLKL protein, human; C570694:MLKL protein, mouse; D011494:Protein Kinases; D002118:Calcium
keywords: ESCRT-III; MLKL; annexin-V; necroptosis; phosphatidylserine; plasma membrane repair