Both cIAP1 and cIAP2 regulate TNFα-mediated NF-κB activation
- 19 August 2008
- journal article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences
- Vol. 105 (33), 11778-11783
- https://doi.org/10.1073/pnas.0711122105
Abstract
The cellular inhibitor of apoptosis 1 and 2 (cIAP1 and cIAP2) proteins have been implicated in the activation of NF-kappaB by TNFalpha; however, genetic deletion of either cIAP1 or 2 did not support a physiologically relevant role, perhaps because of functional redundancy. To address this, we used combined genetic and siRNA knockdown approaches and report that cIAP1 and 2 are indeed critical, yet redundant, regulators of NF-kappaB activation upon TNFalpha treatment. Whereas NF-kappaB was properly activated by TNFalpha in cultured and primary cells deficient in either cIAP1 or 2, removal of both cIAPs severely blunted its activation. After treatment with TNFalpha, cIAP1 and 2 were rapidly recruited to the TNF receptor 1, along with the adapter protein TNF receptor associated factor 2. Importantly, either cIAP1 or 2 was required for proper TNF receptor 1 signalosome function. In their combined absence, polyubiquitination of receptor interacting protein 1, an upstream event necessary for NF-kappaB signaling, was attenuated. As a result, phosphorylation of the inhibitor of kappaB kinase beta was diminished, and signal transduction was severely blunted. Consequently, cells missing both cIAP1 and 2 were sensitized to TNFalpha-mediated apoptosis. Collectively, these data demonstrate that either cIAP1 or 2 is required for proper Rip1 polyubiquitination and NF-kappaB activation upon TNFalpha treatment.Keywords
This publication has 28 references indexed in Scilit:
- IAP Antagonists Target cIAP1 to Induce TNFα-Dependent ApoptosisCell, 2007
- Autocrine TNFα Signaling Renders Human Cancer Cells Susceptible to Smac-Mimetic-Induced ApoptosisCancer Cell, 2007
- Birc2 (cIap1) regulates endothelial cell integrity and blood vessel homeostasisNature Genetics, 2007
- Design, Synthesis, and Biological Activity of a Potent Smac Mimetic That Sensitizes Cancer Cells to Apoptosis by Antagonizing IAPsACS Chemical Biology, 2006
- The Human Anti-apoptotic Proteins cIAP1 and cIAP2 Bind but Do Not Inhibit CaspasesJournal of Biological Chemistry, 2006
- Inhibitor of Apoptosis Protein cIAP2 Is Essential for Lipopolysaccharide-Induced Macrophage SurvivalMolecular and Cellular Biology, 2006
- IKK/NF- B signaling: balancing life and death - a new approach to cancer therapyJCI Insight, 2005
- Cloning and characterization of the rat homologues of the Inhibitor of Apoptosis protein 1, 2, and 3 genes.BMC Genomics, 2002
- Ubiquitin Protein Ligase Activity of IAPs and Their Degradation in Proteasomes in Response to Apoptotic StimuliScience, 2000
- The c-IAP-1 and c-IAP-2 proteins are direct inhibitors of specific caspasesThe EMBO Journal, 1997