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NF-kappaB signaling pathway governs TRAIL gene expression and human T-cell leukemia virus-I Tax-induced T-cell death
I Rivera-Walsh1, M Waterfield, G Xiao
1Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA.
Abstract:
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.
Insights
The Tax oncoprotein triggers T-cell death via NF-kappaB signaling and TRAIL. This study clarifies how Tax manipulates NF-kappaB to induce apoptosis, revealing a crucial mechanism in T-cell leukemia virus infection.
Area of Science:
- Molecular Biology
- Immunology
- Virology
Background:
- The Tax oncoprotein from human T-cell leukemia virus activates T-cells and induces apoptosis.
- The precise mechanism of Tax-mediated apoptosis remains largely unknown.
Purpose of the Study:
- To elucidate the molecular mechanisms by which the Tax oncoprotein induces T-cell apoptosis.
- To investigate the role of NF-kappaB signaling and TRAIL in Tax-induced T-cell death.
Main Methods:
- Utilized genetically manipulated T-cell lines lacking IKKgamma.
- Assessed apoptosis induction in the presence and absence of Tax.
- Employed TRAIL-blocking antibodies to inhibit T-cell death.
- Measured TRAIL mRNA expression levels.
Main Results:
- Tax-induced T-cell apoptosis is critically dependent on NF-kappaB signaling, specifically IKKgamma.
- Defective apoptosis in IKKgamma-deficient cells was rescued by exogenous IKKgamma.
- Tax-induced T-cell death is mediated by TNF-related apoptosis-inducing ligand (TRAIL).
- Tax directly stimulates TRAIL mRNA expression, and NF-kappaB is essential for this induction.
Conclusions:
- The NF-kappaB signaling pathway plays a vital role in Tax-induced T-cell apoptosis.
- TRAIL is a key mediator of Tax-induced T-cell death.
- These findings reveal a novel function for NF-kappaB in viral oncogenesis and T-cell apoptosis.