title: GRIM-19-mediated translocation of STAT3 to mitochondria is necessary for TNF-induced necroptosis.
abstract: Tumor necrosis factor (TNF) can induce necroptosis, wherein inhibition of caspase activity prevents apoptosis but initiates an alternative programmed necrosis. The activity of receptor-interacting serine/threonine-protein kinase 1 (RIPK-1) is required for necroptosis to proceed, with suppression of RIPK-1 expression or inhibition of RIPK-1 activity with necrostatin-1 preventing TNF-induced necroptosis. Downstream from the TNF receptor, the generation of reactive oxygen species at the mitochondria has been identified as necessary for the execution of necroptosis; with antioxidants and inhibitors of mitochondrial complex I preventing TNF-induced cytotoxicity. However, components of the signaling pathway that lie between activated RIPK-1 and the mitochondria are unknown. In the study reported here we demonstrate that during TNF-induced necroptosis, STAT3 is phosphorylated on serine 727, which is dependent on RIPK-1 expression or activity. The phosphorylation of STAT3 induces interaction with GRIM-19, a subunit of mitochondrial complex I, with a resultant translocation of STAT3 to the mitochondria, where it induces an increase in reactive oxygen species production and cell death.
authors.affiliation: Department of Molecular Biology, School of Osteopathic Medicine, University of Medicine and Dentistry of New Jersey, Stratford, New Jersey 08084,  USA.
authors.forename: Nataly
authors.initials: N
authors.lastname: Shulga
authors.forename: John G
authors.initials: JG
authors.lastname: Pastorino
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D051379:Mice; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D009247:NADH, NADPH Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D009336:Necrosis; D010766:Phosphorylation; D021381:Protein Transport; D017382:Reactive Oxygen Species / Q000378:metabolism; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D017382:Reactive Oxygen Species; D050796:STAT3 Transcription Factor; D014409:Tumor Necrosis Factor-alpha; D009247:NADH, NADPH Oxidoreductases; C486684:Grim19 protein, mouse; D053422:Receptor-Interacting Protein Serine-Threonine Kinases