Abstract
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 TNFα, which then activates necroptosis. Here, we describe a novel role for RIP1 kinase in regulating TNFα production after caspase inhibition. Caspase inhibitors activate RIP1 kinase and another protein, EDD, to mediate JNK signaling, which stimulates Sp1-dependent transcription of TNFα. This pathway is independent of nuclear factor κB 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 TNFα production pathway and suggest a novel role for RIP1 kinase in mediating TNFα production under certain conditions.
Highlights
Receptor-interacting protein 1 (RIP1) is ubiquitinated by the cellular inhibitor of apoptosis proteins, cIAP1 and cIAP2.4,5 RIP1 is ubiquitinated by a number of other E3 ubiquitin ligases as well, suggesting that RIP1 ubiquitination might regulate RIP1 activity
In a genome-wide siRNA screen to identify genes involved in necroptosis, we found that knockdown of tnfr[1] or treatment with a TNFa-neutralizing antibody was protective against zVAD.fmk-induced cell death in L929 cells, indicating that zVAD.fmk was likely inducing autocrine TNFa production.[11]
We demonstrate a novel function of RIP1 kinase involving its interaction with EDD to regulate JNK activation and TNFa production
Summary
RIP1 is ubiquitinated by the cellular inhibitor of apoptosis proteins, cIAP1 and cIAP2.4,5 RIP1 is ubiquitinated by a number of other E3 ubiquitin ligases as well, suggesting that RIP1 ubiquitination might regulate RIP1 activity. EDD/UBR5/hHYD is a putative tumor suppressor and HECT (homologous to E6-AP C-terminus)-domain-containing E3 ubiquitin ligase implicated in cellular pathways including the regulation of gene expression, the DNA damage response, and in necroptosis after it was identified in a siRNA screen.[11,12] EDD regulates gene expression transcriptionally, by forming complexes with transcription factors, and translationally by regulating protein levels of Paip[2], a poly-A-binding protein inhibitor.[13,14] EDD is important in the cellular DNA damage response, mediating ATM phosphorylation of its substrates CHK2 and p53 after DNA damage to control cell cycle arrest.[15,16,17] Given its multiple functions in mediating cellular processes, EDD likely acts as a chaperone protein, coordinating the various protein complexes involved in different cellular pathways. This TNFa production pathway requires RIP1 kinase and is activated in response to zVAD.fmk stimulation, SM compounds, or TNF receptorassociated factor 2 (Traf2) deficiency
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