title: Mitochondrial translocation of oxidized cofilin induces caspase-independent necrotic-like programmed cell death of T cells.
abstract: Oxidative stress leads to T-cell hyporesponsiveness or death. The actin-binding protein cofilin is oxidized during oxidative stress, which provokes a stiff actin cytoskeleton and T-cell hyporesponsiveness. Here, we show that long-term oxidative stress leads to translocation of cofilin into the mitochondria and necrotic-like programmed cell death (PCD) in human T cells. Notably, cofilin mutants that functionally mimic oxidation by a single mutation at oxidation-sensitive cysteins (Cys-39 or Cys-80) predominately localize within the mitochondria. The expression of these mutants alone ultimately leads to necrotic-like PCD in T cells. Accordingly, cofilin knockdown partially protects T cells from the fatal effects of long-term oxidative stress. Thus, we introduce the oxidation and mitochondrial localization of cofilin as the checkpoint for necrotic-like PCD upon oxidative stress as it occurs, for example, in tumor environments.
authors.affiliation: Institute for Immunology, Ruprecht-Karls-University, Heidelberg, Germany. guido.wabnitz@immu.uni-heidelberg.de
authors.forename: G H
authors.initials: GH
authors.lastname: Wabnitz
authors.forename: C
authors.initials: C
authors.lastname: Goursot
authors.forename: B
authors.initials: B
authors.lastname: Jahraus
authors.forename: H
authors.initials: H
authors.lastname: Kirchgessner
authors.forename: A
authors.initials: A
authors.lastname: Hellwig
authors.forename: M
authors.initials: M
authors.lastname: Klemke
authors.forename: M H
authors.initials: MH
authors.lastname: Konstandin
authors.forename: Y
authors.initials: Y
authors.lastname: Samstag
mesh_terms: D017209:Apoptosis; D020169:Caspases / Q000378:metabolism*; D002478:Cells, Cultured; D051338:Cofilin 1 / Q000235:genetics / Q000378:metabolism*; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008928:Mitochondria / Q000378:metabolism*; D009336:Necrosis / Q000378:metabolism*; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*
chemical_list: D051338:Cofilin 1; D018840:HSP70 Heat-Shock Proteins; D034741:RNA, Small Interfering; D006861:Hydrogen Peroxide; D020169:Caspases