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.
Highlights
Necroptosis is a form of regulated cell death that displays all the major hallmarks of necrosis [1]
While necroptosis was initially identified as a back-up form of cell death triggered by pro-apoptotic stimuli in the presence of apoptosis inhibitors [17], recent analysis of physiological cell death during mouse development has suggested that the loss of apoptotic regulators, such as caspase-8 and Fas-associated protein with death domain (FADD) [18,19,20], leads to robust induction of necroptosis and death of E10.5 embryos even though apoptosis is not normally induced in wild type embryos
We demonstrated that selective necroptotic phosphorylation of Thr308 of Akt is sufficient to increase its activity towards a number of known substrates and Akt effector pathways such as the mammalian Target of Rapamycin complex 1 (mTORC1) pathway, which, in turn, contributes to cell death
Summary
Necroptosis is a form of regulated cell death that displays all the major hallmarks of necrosis [1]. Akt kinase, a key pro-survival molecule and a well-established inhibitor of apoptotic cell death, has recently been linked to necroptosis in L929 cells [16], where insulin-dependent activation of Akt was suggested to promote necroptosis by suppressing autophagy. This conclusion was unexpected, since several reports from different groups, including ours, have established that autophagy promotes, rather than suppresses, zVAD.fmk-induced necroptosis in L929 cells [11,14,17]. The key question of whether insulin-dependent Akt activity solely provides an environment conducive for necroptosis or if Akt activation is an intrinsic component of necroptosis signaling that is linked to RIP1 kinase has not been explored
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