The zinc finger protein A20 inhibits TNF-induced NF-kappaB-dependent gene expression by interfering with an RIP- or TRAF2-mediated transactivation signal and directly binds to a novel NF-kappaB-inhibiting protein ABIN.
The zinc finger protein A20 is a tumor necrosis factor (TNF)- and interleukin 1 (IL-1)-inducible protein that negatively regulates nuclear factor-kappa B (NF-kappaB)-dependent gene expression. However, the molecular mechanism by which A20 exerts this effect is still unclear. We show that A20 does not inhibit TNF- induced nuclear translocation and DNA binding of NF-kappaB, although it completely prevents the TNF- induced activation of an NF-kappaB-dependent reporter gene, as well as TNF-induced IL-6 and granulocyte macrophage-colony stimulating factor gene expression. Moreover, NF-kappaB activation induced by overexpression of the TNF receptor-associated proteins TNF receptor-associated death domain protein (TRADD), receptor interacting protein (RIP), and TNF recep- tor-associated factor 2 (TRAF2) was also inhibited by expression of A20, whereas NF-kappaB activation induced by overexpression of NF-kappaB-inducing kinase (NIK) or the human T cell leukemia virus type 1 (HTLV-1) Tax was unaffected. These results demonstrate that A20 inhibits NF-kappaB-dependent gene expression by interfering with a novel TNF-induced and RIP- or TRAF2-mediated pathway that is different from the NIK-IkappaB kinase pathway and that is specifically involved in the transactivation of NF-kappaB. Via yeast two-hybrid screening, we found that A20 binds to a novel protein, ABIN, which mimics the NF-kappaB inhibiting effects of A20 upon overexpression, suggesting that the effect of A20 is mediated by its interaction with this NF-kappaB inhibiting protein, ABIN.
Heyninck
K
K
Department of Molecular Biology, Flanders Interuniversity Institute for Biotechnology, University of Ghent, B-9000 Ghent, Belgium.
De Valck
D
D
Vanden Berghe
W
W
Van Criekinge
W
W
Contreras
R
R
Fiers
W
W
Haegeman
G
G
Beyaert
R
R
D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D003546:Cysteine Endopeptidases; D004247:DNA / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins; D004789:Enzyme Activation / Q000187:drug effects; D016356:Gene Products, tax / Q000235:genetics / Q000378:metabolism; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D020928:Mitogen-Activated Protein Kinases; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology; D011485:Protein Binding / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D011506:Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D015398:Signal Transduction / Q000187:drug effects; D053199:TNF Receptor-Associated Death Domain Protein; D047990:TNF Receptor-Associated Factor 1; D047992:TNF Receptor-Associated Factor 2; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology; D015533:Transcriptional Activation / Q000187:drug effects; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D015003:Yeasts / Q000235:genetics; D016335:Zinc Fingers; D048051:p38 Mitogen-Activated Protein Kinases; D000097782:NF-kappaB-Inducing Kinase
D017871:Calcium-Calmodulin-Dependent Protein Kinases; D002352:Carrier Proteins; D003546:Cysteine Endopeptidases; D004247:DNA; D004268:DNA-Binding Proteins; D016356:Gene Products, tax; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D015850:Interleukin-6; D047908:Intracellular Signaling Peptides and Proteins; D020928:Mitogen-Activated Protein Kinases; D016328:NF-kappa B; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; D011506:Proteins; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D053199:TNF Receptor-Associated Death Domain Protein; D047990:TNF Receptor-Associated Factor 1; D047992:TNF Receptor-Associated Factor 2; D015534:Trans-Activators; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases; D000097782:NF-kappaB-Inducing Kinase; C481226:Tradd protein, mouse; C506249:RIPK1 protein, human; C506251:Ripk1 protein, mouse; C076529:TNFAIP3 protein, human; C513261:Tnfaip3 protein, mouse