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.
Storz
Peter
P
Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA. pstorz@bidmc.harvard.edu
Döppler
Heike
H
Ferran
Christiane
C
Grey
Shane T
ST
Toker
Alex
A
D017209:Apoptosis / Q000502:physiology*; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins; D006367:HeLa Cells / Q000737:chemistry / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D009336:Necrosis / Q000473:pathology; D009687:Nuclear Proteins; D018384:Oxidative Stress / Q000502:physiology; D011506:Proteins / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D009687:Nuclear Proteins; D011506:Proteins; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; C076529:TNFAIP3 protein, human; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3