Functional dichotomy of A20 in apoptotic and necrotic cell death.

ROS (reactive oxygen species) play important roles in the progression of a number of human pathologies. ROS promote cell death, but can also induce gene transcription. The transcription factor NF-kappaB (nuclear factor kappaB) plays a critical role in oxidative stress responses. One of the proteins regulated by NF-kappaB is the zinc-finger protein A20. In TNF (tumour necrosis factor)-alpha signalling, NF-kappaB induction of A20 leads to increased cell survival. In the present paper, we show that in response to oxidative stress, A20 actually enhances cell death by necrosis, but not by apoptosis. Exposure of cells to ROS leads to the up-regulation of A20 which acts via a negative-feedback loop to block NF-kappaB activation and cellular survival. Silencing of A20 by RNAi (RNA interference) increases both the induction of NF-kappaB and the subsequent survival of cells exposed to high doses of oxidative stress, which, in untreated cells, promotes death by necrosis. Cells which express high basal levels of A20 are less protected from oxidative-stress-induced cell death when compared with cells with lower A20 expression. We also show that A20 regulates NF-kappaB by blocking the degradation of IkappaB (inhibitory protein kappaB) alpha. These data highlight a novel role for A20 in oxidative stress responses by terminating NF-kappaB-dependent survival signalling and thus sensitizing cells to death by necrosis.

[1]  A. Meister Selective modification of glutathione metabolism. , 1983, Science.

[2]  V. Dixit,et al.  The A20 zinc finger protein protects cells from tumor necrosis factor cytotoxicity. , 1992, The Journal of biological chemistry.

[3]  Carol D. Laherty,et al.  Human T cell leukemia virus type I Tax and phorbol 12-myristate 13-acetate induce expression of the A20 zinc finger protein by distinct mechanisms involving nuclear factor kappa B. , 1993, The Journal of biological chemistry.

[4]  George Kollias,et al.  The transmembrane form of tumor necrosis factor is the prime activating ligand of the 80 kDa tumor necrosis factor receptor , 1995, Cell.

[5]  M. Jäättelä,et al.  A20 zinc finger protein inhibits TNF and IL-1 signaling. , 1996, Journal of immunology.

[6]  C. Ferran,et al.  A20 Blocks Endothelial Cell Activation through a NF-κB-dependent Mechanism* , 1996, The Journal of Biological Chemistry.

[7]  Vijay R Baichwal,et al.  Apoptosis: Activate NF-κB or die? , 1997, Current Biology.

[8]  A. Manning,et al.  NF-κB as a primary regulator of the stress response , 1999, Oncogene.

[9]  Michael Karin,et al.  Is NF‐κB the sensor of oxidative stress? , 1999 .

[10]  J. Engelhardt Redox-mediated gene therapies for environmental injury: approaches and concepts. , 1999, Antioxidants & redox signaling.

[11]  C. Ferran,et al.  A20 Inhibits Cytokine-Induced Apoptosis and Nuclear Factor κB–Dependent Gene Activation in Islets , 1999, The Journal of experimental medicine.

[12]  R. Contreras,et al.  The Zinc Finger Protein A20 Inhibits TNF-induced NF-κB–dependent Gene Expression by Interfering with an RIP- or TRAF2-mediated Transactivation Signal and Directly Binds to a Novel NF-κB–inhibiting Protein ABIN , 1999, The Journal of cell biology.

[13]  M. Karin How NF-κB is activated: the role of the IκB kinase (IKK) complex , 1999, Oncogene.

[14]  R. Beyaert,et al.  A20 and A20-binding proteins as cellular inhibitors of nuclear factor-kappa B-dependent gene expression and apoptosis. , 2000, Biochemical pharmacology.

[15]  J. Piette,et al.  Crucial Role of the Amino-Terminal Tyrosine Residue 42 and the Carboxyl-Terminal PEST Domain of IκBα in NF-κB Activation by an Oxidative Stress1 , 2000, The Journal of Immunology.

[16]  G Cantarella,et al.  Recruitment of the IKK signalosome to the p55 TNF receptor: RIP and A20 bind to NEMO (IKKgamma) upon receptor stimulation. , 2000, Immunity.

[17]  A. Ma,et al.  Failure to regulate TNF-induced NF-kappaB and cell death responses in A20-deficient mice. , 2000, Science.

[18]  A. Israël The IKK complex: an integrator of all signals that activate NF-κB? , 2000 .

[19]  Yong Li,et al.  A20 INHIBITS NF-κB ACTIVATION DOWNSTREAM OF MULTIPLE MAP3 KINASES AND INTERACTS WITH THE IκB SIGNALOSOME , 2001 .

[20]  U. Schlecht,et al.  Endogenous Membrane Tumor Necrosis Factor (TNF) Is a Potent Amplifier of TNF Receptor 1-mediated Apoptosis* , 2002, The Journal of Biological Chemistry.

[21]  C. Albanese,et al.  E2F1 and c-Myc potentiate apoptosis through inhibition of NF-kappaB activity that facilitates MnSOD-mediated ROS elimination. , 2002, Molecular cell.

[22]  R. Bernards,et al.  A System for Stable Expression of Short Interfering RNAs in Mammalian Cells , 2002, Science.

[23]  G. Georgiou How to Flip the (Redox) Switch , 2002, Cell.

[24]  Geert J. P. L. Kops,et al.  Forkhead transcription factor FOXO3a protects quiescent cells from oxidative stress , 2002, Nature.

[25]  A. Ting,et al.  A20 Inhibits Tumor Necrosis Factor (TNF) Alpha-Induced Apoptosis by Disrupting Recruitment of TRADD and RIP to the TNF Receptor 1 Complex in Jurkat T Cells , 2002, Molecular and Cellular Biology.

[26]  Peter Storz,et al.  Protein kinase D mediates a stress‐induced NF‐κB activation and survival pathway , 2003, The EMBO journal.

[27]  J. Engelhardt,et al.  Tyrosine Phosphorylation of IκBα Activates NFκB through a Redox-regulated and c-Src-dependent Mechanism Following Hypoxia/Reoxygenation* , 2003, The Journal of Biological Chemistry.

[28]  T. Finkel Oxidant signals and oxidative stress. , 2003, Current opinion in cell biology.

[29]  T. Blundell,et al.  A Novel Type of Deubiquitinating Enzyme* , 2003, Journal of Biological Chemistry.

[30]  A. Toker,et al.  Tyrosine Phosphorylation of Protein Kinase D in the Pleckstrin Homology Domain Leads to Activation* , 2003, The Journal of Biological Chemistry.

[31]  A. Toker,et al.  NF-κB Signaling: An ALternate Pathway for Oxidate Stress Responses , 2003, Cell cycle.

[32]  F. Weih,et al.  NFκB Controls the Balance between Fas and Tumor Necrosis Factor Cell Death Pathways during T Cell Receptor-induced Apoptosis Via the Expression of Its Target Gene A20* , 2003, Journal of Biological Chemistry.

[33]  R. Beyaert,et al.  Structure–function analysis of the A20‐binding inhibitor of NF‐κB activation, ABIN‐1 , 2003 .

[34]  H. Ploegh,et al.  Zinc-finger protein A20, a regulator of inflammation and cell survival, has de-ubiquitinating activity. , 2004, The Biochemical journal.

[35]  Somasekar Seshagiri,et al.  De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-κB signalling , 2004, Nature.

[36]  A. Toker,et al.  Protein Kinase C Selectively Regulates Protein Kinase D-Dependent Activation of NF- B in Oxidative Stress Signaling , 2004 .