Akt Regulates TNF alpha Synthesis Downstream of RIP1 Kinase Activation during Necroptosis

作者：McNamara Colleen R; Ahuja Ruchita; Osafo Addo Awo D; Barrows Douglas; Kettenbach Arminja; Skidan Igor; Teng Xin; Cuny Gregory D; Gerber Scott; Degterev Alexei^*

来源：PLos One, 2013, 8(3): e56576.

DOI：10.1371/journal.pone.0056576

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 TNF alpha 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 TNF alpha. In other cell types, such as mouse lung fibroblasts and macrophages, Akt exhibited control over necroptosis-associated TNF alpha 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.

• 出版日期2013-3-1