title: A receptor-interacting protein 1 (RIP1)-independent necrotic death under the control of protein phosphatase PP2A that involves the reorganization of actin cytoskeleton and the action of cofilin-1.
abstract: Cell death by necrosis is emerging not merely as a passive phenomenon but as a cell-regulated process. Here, by using different necrotic triggers, we prove the existence of two distinct necrotic pathways. The mitochondrial reactive oxygen species generator 2,3-dimethoxy-1,4-naphthoquinone elicits necrosis characterized by the involvement of RIP1 and Drp1. However, G5, a non-selective isopeptidase inhibitor, triggers a distinct necrotic pathway that depends on the protein phosphatase PP2A and the actin cytoskeleton. PP2A catalytic subunit is stabilized by G5 treatment, and its activity is increased. Furthermore, PP2Ac accumulates into the cytoplasm during necrosis similarly to HMGB1. We have also defined in the actin-binding protein cofilin-1 a link between PP2A, actin cytoskeleton, and necrotic death. Cofilin-1-severing/depolymerization activity is negatively regulated by phosphorylation of serine 3. PP2A contributes to the dephosphorylation of serine 3 elicited by G5. Finally, a cofilin mutant that mimics phosphorylated Ser-3 can partially rescue necrosis in response to G5.
authors.affiliation: From the Dipartimento di Scienze Mediche e Biologiche Università degli Studi di Udine, P.le Kolbe 4-33100 Udine, Italy and.
authors.forename: Andrea
authors.initials: A
authors.lastname: Tomasella
authors.affiliation: CNRS UMR 5237 CRBM Montpellier University 1919 Route de Mende, 34293 Montpellier Cedex 5, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Blangy
authors.affiliation: From the Dipartimento di Scienze Mediche e Biologiche Università degli Studi di Udine, P.le Kolbe 4-33100 Udine, Italy and claudio.brancolini@uniud.it.
authors.forename: Claudio
authors.initials: C
authors.lastname: Brancolini
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism* / Q000648:ultrastructure; D051339:Actin Depolymerizing Factors / Q000737:chemistry; D021961:Cell Membrane Structures / Q000737:chemistry / Q000187:drug effects; D051338:Cofilin 1 / Q000737:chemistry / Q000378:metabolism*; D019073:HT29 Cells; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009336:Necrosis / Q000235:genetics / Q000378:metabolism; D028861:Nuclear Pore Complex Proteins / Q000737:chemistry / Q000378:metabolism*; D054648:Protein Phosphatase 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D059748:Proteolysis; D011714:Pyrans / Q000494:pharmacology; D016601:RNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013438:Sulfhydryl Compounds / Q000494:pharmacology
chemical_list: C540769:4H-thiopyran-4-one tetrahydro-3,5-bis-((4-nitrophenyl)methylene)-1,1-dioxide; C119724:AGFG1 protein, human; D051339:Actin Depolymerizing Factors; D051338:Cofilin 1; D028861:Nuclear Pore Complex Proteins; D011714:Pyrans; D016601:RNA-Binding Proteins; D017382:Reactive Oxygen Species; D013438:Sulfhydryl Compounds; D054648:Protein Phosphatase 2
keywords: Actin; Cofilin; Necrosis (Necrotic Death); Protein Degradation; Protein Phosphatase 2 (PP2A)
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