Inactivation of IκBβ by the Tax Protein of Human T-Cell Leukemia Virus Type 1: a Potential Mechanism for Constitutive Induction of NF-κB

In resting T lymphocytes, the transcription factor NF-κB is sequestered in the cytoplasm via interactions with members of the IκB family of inhibitors, including IκBα and IκBβ. During normal T-cell activation, IκBα is rapidly phosphorylated, ubiquitinated, and degraded by the 26S proteasome, thus permitting the release of functional NF-κB. In contrast to its transient pattern of nuclear induction during an immune response, NF-κB is constitutively activated in cells expressing the Tax transforming protein of human T-cell leukemia virus type 1 (HTLV-1). Recent studies indicate that HTLV-1 Tax targets IκBα to the ubiquitin-proteasome pathway. However, it remains unclear how this viral protein induces a persistent rather than transient NF-κB response. In this report, we provide evidence that in addition to acting on IκBα, Tax stimulates the turnover of IκBβ via a related targeting mechanism. Like IκBα, Tax-mediated breakdown of IκBβ in transfected T lymphocytes is blocked either by cell-permeable proteasome inhibitors or by mutation of IκBβ at two serine residues present within its N-terminal region. Despite the dual specificity of HTLV-1 Tax for IκBα and IκB I at the protein level, Tax selectively stimulates NF-KB-directed transcription of the IκBα gene. Consequently, κB I protein expression is chronically downregulated in HTLV-1-infected T lymphocytes. These findings with κBβ provide a potential mechanism for the constitutive activation of NF-κB in Tax-expressing cells.