NF-kappaB signaling pathway governs TRAIL gene expression and human T-cell leukemia virus-I Tax-induced T-cell death.
The Tax oncoprotein encoded by human T-cell leukemia virus induces both T-cell activation and apoptosis. The mechanism by which Tax induces apoptosis has remained unclear. Using genetically manipulated T-cell lines, we demonstrate that Tax-induced T-cell death is dependent on NF-kappaB signaling. Tax fails to induce apoptosis in T cells lacking IkappaB kinase gamma (IKKgamma), an essential component of the NF-kappaB signaling pathway. This defect was rescued when the mutant cells were reconstituted with exogenous IKKgamma. We further demonstrate that the Tax-induced T-cell death is mediated by TNF (tumor necrosis factor)-related apoptosis-inducing ligand (TRAIL), because this event can be effectively inhibited by a TRAIL-blocking antibody. Consistent with this functional aspect, Tax stimulates the expression of TRAIL mRNA. Finally, we provide genetic evidence demonstrating that the NF-kappaB signaling pathway is essential for TRAIL gene induction by both Tax and T-cell activation signals. These studies reveal a novel function of the NF-kappaB signaling pathway and suggest a key mechanism by which Tax induces T-cell death.
Rivera-Walsh
I
I
Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA.
Waterfield
M
M
Xiao
G
G
Fong
A
A
Sun
S C
SC
D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins; D001483:Base Sequence; D017931:DNA Primers; D005786:Gene Expression Regulation / Q000502:physiology*; D016356:Gene Products, tax / Q000502:physiology*; D006801:Humans; D019169:Jurkat Cells; D008562:Membrane Glycoproteins / Q000235:genetics*; D016328:NF-kappa B / Q000378:metabolism* / Q000502:physiology; D012333:RNA, Messenger / Q000235:genetics; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology*; D053221:TNF-Related Apoptosis-Inducing Ligand; D015533:Transcriptional Activation; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
D051017:Apoptosis Regulatory Proteins; D017931:DNA Primers; D016356:Gene Products, tax; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D012333:RNA, Messenger; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha