Identification of a ZU5 and death domain-containing inhibitor of NF-kappaB.
The transcription factor NF-kappaB plays important roles in inflammation and cell survival. NF-kappaB is composed of homodimeric and heterodimeric complexes of Rel/NF-kappaB family members, including p65 (RelA), c-Rel (Rel), RelB, NF-kappaB1/p50, and NF-kappaB2/p52. Here we report the identification and characterization of a novel ZU5 and death domain-containing protein designated ZUD. In reporter gene assays, overexpression of ZUD inhibited NF-kappaB-dependent transcription induced by both tumor necrosis factor (TNF) and interleukin-1 and their downstream signaling proteins. Gel shift assays indicated that the overexpression of ZUD inhibited binding of NF-kappaB to its target sequence. ZUD is a cytoplasmic protein, and coimmunoprecipitation assays indicated that ZUD interacted with the NF-kappaB subunit p105 and transactivator p65. Consistent with its role in inhibition of NF-kappaB-dependent transcription, ZUD sensitized cells to apoptosis induced by TNF and the TNF-related apoptosis-inducing ligand (TRAIL). Our findings suggest that ZUD is an inhibitor of NF-kappaB activation and that this protein may provide an alternative regulatory mechanism for NF-kappaB-mediated transcription.
Zhang
Jun
J
Department of Immunology, National Jewish Medical and Research Center, University of Colorado Health Sciences Center, Denver, Colorado 80206, USA.
Xu
Liang-Guo
LG
Han
Ke-Jun
KJ
Shu
Hong-Bing
HB
D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D015152:Blotting, Northern; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics* / Q000502:physiology*; D002460:Cell Line; D003001:Cloning, Molecular; D003593:Cytoplasm / Q000378:metabolism; D017353:Gene Deletion; D017930:Genes, Reporter; D005822:Genetic Vectors; D006801:Humans; D007375:Interleukin-1 / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins / Q000378:metabolism; D008856:Microscopy, Fluorescence; D008957:Models, Genetic; D008969:Molecular Sequence Data; D009154:Mutation; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D053221:TNF-Related Apoptosis-Inducing Ligand; D014018:Tissue Distribution; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; D007375:Interleukin-1; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; C505654:Tnfsf10 protein, mouse; D014409:Tumor Necrosis Factor-alpha; C486467:UNC5CL protein, human; C486466:Unc5cl protein, mouse