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J. Biol. Chem., Vol. 276, Issue 44, 40385-40388, November 2, 2001

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ACCELERATED PUBLICATION
NF-B Signaling Pathway Governs TRAIL Gene Expression and Human T-cell Leukemia Virus-I Tax-induced T-cell Death^*

Isis Rivera-Walsh, Michael Waterfield, Gutian Xiao, Abraham Fong, and Shao-Cong Sun

From the Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033

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-B signaling. Tax fails to induce apoptosis in T cells lacking IB kinase  (IKK), an essential component of the NF-B signaling pathway. This defect was rescued when the mutant cells were reconstituted with exogenous IKK. 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-B 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-B signaling pathway and suggest a key mechanism by which Tax induces T-cell death.

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