title: Akt Regulates TNFα synthesis downstream of RIP1 kinase activation during necroptosis.
abstract: Necroptosis is a regulated form of necrotic cell death that has been implicated in the pathogenesis of various diseases including intestinal inflammation and systemic inflammatory response syndrome (SIRS). In this work, we investigated the signaling mechanisms controlled by the necroptosis mediator receptor interacting protein-1 (RIP1) kinase. We show that Akt kinase activity is critical for necroptosis in L929 cells and plays a key role in TNFα production. During necroptosis, Akt is activated in a RIP1 dependent fashion through its phosphorylation on Thr308. In L929 cells, this activation requires independent signaling inputs from both growth factors and RIP1. Akt controls necroptosis through downstream targeting of mammalian Target of Rapamycin complex 1 (mTORC1). Akt activity, mediated in part through mTORC1, links RIP1 to JNK activation and autocrine production of TNFα. In other cell types, such as mouse lung fibroblasts and macrophages, Akt exhibited control over necroptosis-associated TNFα production without contributing to cell death. Overall, our results provide new insights into the mechanism of necroptosis and the role of Akt kinase in both cell death and inflammatory regulation.
authors.affiliation: Graduate Program in Biochemistry, Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, Massachussets, United States of America.
authors.forename: Colleen R
authors.initials: CR
authors.lastname: McNamara
authors.forename: Ruchita
authors.initials: R
authors.lastname: Ahuja
authors.forename: Awo D
authors.initials: AD
authors.lastname: Osafo-Addo
authors.forename: Douglas
authors.initials: D
authors.lastname: Barrows
authors.forename: Arminja
authors.initials: A
authors.lastname: Kettenbach
authors.forename: Igor
authors.initials: I
authors.lastname: Skidan
authors.forename: Xin
authors.initials: X
authors.lastname: Teng
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Cuny
authors.forename: Scott
authors.initials: S
authors.lastname: Gerber
authors.forename: Alexei
authors.initials: A
authors.lastname: Degterev
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002460:Cell Line; D004789:Enzyme Activation; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D006801:Humans; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D046912:Multiprotein Complexes; D009336:Necrosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics* / Q000378:metabolism; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases; D013912:Threonine / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D046912:Multiprotein Complexes; D011506:Proteins; D014409:Tumor Necrosis Factor-alpha; D013912:Threonine; D000076222:Mechanistic Target of Rapamycin Complex 1; D051057:Proto-Oncogene Proteins c-akt; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C506251:Ripk1 protein, mouse; D058570:TOR Serine-Threonine Kinases; D020928:Mitogen-Activated Protein Kinases