A novel role for RIP1 kinase in mediating TNFα production

Receptor-interacting protein 1 (RIP1) is a Ser/Thr kinase with both kinase-dependent and kinase-independent roles in death receptor signaling. The kinase activity of RIP1 is required for necroptosis, a caspase-independent pathway of programmed cell death. In some cell types, the inhibition of caspases leads to autocrine production of TNF alpha, which then activates necroptosis. Here, we describe a novel role for RIP1 kinase in regulating TNF alpha production after caspase inhibition. Caspase inhibitors activate RIP1 kinase and another protein, EDD, to mediate JNK signaling, which stimulates Sp1-dependent transcription of TNF alpha. This pathway is independent of nuclear factor kappa B and also occurs after Smac mimetic/IAP antagonist treatment or the loss of TNF receptor-associated factor 2 (Traf2). These findings implicate cIAP1/2 and Traf2 as negative regulators of this RIP1 kinase-dependent TNF alpha production pathway and suggest a novel role for RIP1 kinase in mediating TNF alpha production under certain conditions. Cell Death and Disease (2012) 3, e320; doi:10.1038/cddis.2012.64; published online 14 June 2012