Inhibition of tumor necrosis factor-induced necrotic cell death by the zinc finger protein A20.
Tumor Necrosis Factor (TNF) is a cytokine that induces necrotic and apoptotic forms of cell death. The TNF-induced signalling mechanisms leading to necrosis or apoptosis are partially distinct, and are therefore likely to be regulated in a different way. The zinc finger protein A20 is a TNF-induced primary response gene that has been shown to inhibit TNF-induced apoptosis. However, its ability to inhibit the necrotic route of cell death as well as the underlying mechanism remains unknown. Here we show that stable expression of A20 or a fusion protein consisting of Green Fluorescent Protein (GFP) and A20 protects the TNF-sensitive fibroblast cell line L929 partially from TNF-induced necrotic cell death. TNF-induced necrosis has been shown to involve the activation of several phospholipases, as well as an increased production of reactive oxygen radicals. The reduced TNF-sensitivity of A20-expressing L929 cells was correlated with a decrease of TNF-induced phospholipase A2 (PLA2), phospholipase C (PLC) and phospholipase D (PLD) activation. Furthermore, production of mitochondrial reactive oxygen intermediates was retarded by overexpression of A20. These results demonstrate that A20 not only inhibits TNF-induced apoptosis but also TNF-induced necrosis, suggesting that it interferes with an early step in TNF signalling which is required for both types of cell death.
Heyninck
K
K
Department of Molecular Biology, Flanders Interuniversity Institute for Biotechnology, Gent, Belgium.
Denecker
G
G
De Valck
D
D
Fiers
W
W
Beyaert
R
R
D000818:Animals; D016923:Cell Death / Q000502:physiology*; D003546:Cysteine Endopeptidases; D004789:Enzyme Activation; D005354:Fibrosarcoma / Q000201:enzymology / Q000473:pathology; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D009336:Necrosis; D009687:Nuclear Proteins; D010740:Phospholipases / Q000378:metabolism; D011506:Proteins / Q000502:physiology*; D017382:Reactive Oxygen Species; D014407:Tumor Cells, Cultured; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000502:physiology; D016335:Zinc Fingers
D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D011506:Proteins; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D010740:Phospholipases; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D003546:Cysteine Endopeptidases; C513261:Tnfaip3 protein, mouse