Activation of IKKα and IKKβ through their fusion with HTLV-I Tax protein

Abstract

Human T-cell leukemia virus type I (HTLV-I) Tax protein persistently stimulates the activity of IκB kinase (IKK), resulting in constitutive activation of the transcription factor NF-κB. Tax activation of IKK requires physical interaction of this viral protein with the IKK regulatory subunit, IKKγ. The Tax/IKKγ interaction allows Tax to engage the IKK catalytic subunits, IKKα and IKKβ, although it remains unclear whether this linker function of IKKγ is sufficient for supporting the Tax-specific IKK activation. To address this question, we have examined the sequences of IKKγ required for modulating the Tax/IKK signaling. We demonstrate that when fused to Tax, a small N-terminal fragment of IKKγ, containing its minimal IKKα/β-binding domain, is sufficient for bringing Tax to and activating the IKK catalytic subunits. Disruption of the IKKα/β-binding activity of this domain abolishes its function in modulating the Tax/IKK signaling. We further demonstrate that direct fusion of Tax to IKKα and IKKβ leads to activation of these kinases. These findings suggest that the IKKγ-directed Tax/IKK association serves as a molecular trigger for IKK activation.