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

Abstract

In resting T lymphocytes, the transcription factor NF-B isHuman T-cell leukemia virus type 1 (HTLV-1) is the causative agent of adult T-cell leukemia, an aggressive and often fatal malignancy of activated CD4 ϩ T lymphocytes (54, 82). This oncogenic retrovirus encodes a 40-kDa protein, termed Tax, which appears to play a central role in the process of neoplastic transformation (31,50,55,69,75). In this regard, Tax has the capacity to constitutively activate members of the NF-B/Rel family of transcription factors (5,44,59). This virus-host interplay confers Tax inducibility to a set of NF-Bresponsive cellular genes that are normally transcribed at high levels in response to T-cell activation signals. These genes include those encoding the growth factor interleukin-2 (IL-2) and the alpha subunit of its high-affinity receptor (19,35,39,45,67; for reviews, see references 27 and 28). Recent studies with mice transgenic for the tax gene suggest that the constitutive nuclear pattern of NF-B expression in HTLV-1-infected cells is required to maintain a state of deregulated growth (40). However, the precise mechanism by which Tax induces NF-B remains unclear.The prototypic form of NF-B is a heterodimeric complex containing p50 (NF-B1) and RelA (p65) (4,12,26,38,46,52,57). In resting T lymphocytes, NF-B is sequestered in the cytoplasm by virtue of its association with members of a set of inhibitory proteins, including IB␣ (2-4, 9, 23). During normal T-cell activation, IB␣ is rapidly phosphorylated at Ser-32 and Ser-36 (13, 14, 78), which is a prerequisite for targeting this inhibitor to the ubiquitin-proteasome pathway (16, 62; reviewed in reference 22). Several lines of evidence indicate that Tax stimulates the phosphorylation and degradation of IB␣ via a similar mechanism. First, IB␣ mutants containing alanine substitutions at Ser-32 and Ser-36 escape from proteolytic breakdown and prevent NF-B activation in Tax-expressing cells (13). Second, Tax fails to activate latent NF-B complexes containing mutant forms of IB␣ that are defective for ubiquitination (62). Third, point mutations in Tax that ablate its NF-B-inducing activity also impair its ability to stimulate IB␣ turnover (13). Fourth, phosphorylated IB␣ accumulates in Tax-expressing cells following treatment with an inhibitor of the proteasome (13). Together, these findings indicate that cytoplasmic NF-B complexes containing IB␣ serve as a major cellular target of HTLV-1 Tax.Recent molecular cloning studies have revealed another conditionally labile isoform of IB, termed IB␤, which has significant sequence homology with IB␣ (77). Although IB␣ and IB␤ likely interact with the same set of NF-B/Rel family members, it appears that these two inhibitors display distinct responses to different inducers of NF-B activity (77). As previously reported (77), agonists that stimulate a transient pattern of NF-B activity promote the selective breakdown of IB␣. In contrast, agents that elicit a persistent NF-B response, including bacterial lipopolysaccharide (LPS) and IL-1, are as...

High-level expression of IkB-b in the surface epithelium of the colon: in vitro evidence for an immunomodulatory role

“…4). Indeed, co-transfection studies by McKinsey et al have shown that I B-␤ over-expression can directly inhibit RelA transactivation of a heterologous promoter containing HIV-1 B enhancer cassette [57]. Finally, we have shown that the induction of mRNA expression of a second chemokine, monocyte chemotactic protein-1 (MCP-1), by IL-1␤ in Caco-2 cells is also inhibited by sodium butyrate in a dose-dependent fashion [12].…”

HTLV-I Tax transrepresses the human c-Myb promoter independently of its interaction with CBP or p300

“…Speci®city of the antibody to p300 was con®rmed by the absence of Tax in the immunoprecipitate when p300 was incubated with Luciferase protein (Luciferase) or when Tax protein was incubated in the absence of p300 (control). proteins such as IkBa and IkBb to the ubiquitinproteasome degradation pathway (Brockman et al, 1995;McKinsey et al, 1996). However, c-Myb expression was not signi®cantly a ected when CMVc-Myb and CMV Tax were co-expressed in transient transfection assays (Figure 5b), suggesting that Tax suppression of c-Myb transactivation potential and the consequent repression of the c-Myb promoter are not direct consequences of a decrease in c-Myb at the protein level.…”

Comparative biology of human T-cell lymphotropic virus type 1 (HTLV-1) and HTLV-2

“…Of the factors targeted by Tax, NFkB clearly plays a prominent role in deregulation of cellular gene expression. Tax induces the nuclear expression of members of the NFkB family of transcription factors, which leads to expression of many gene promoters containing NFkB motifs (Lacoste et al, 1991;Lindholm et al, 1991;Li et al, 1993;Kanno et al, 1994;Brockman et al, 1995;Maggirwar et al, 1995;McKinsey et al, 1996). These genes include those encoding interleukin-2 (IL-2), IL-2 receptor a (IL2Ra), IL-3, GM-CSF, as well as HIV-1 (Siekevitz et al, 1987;Ballard et al, 1988;Leung and Nabel, 1988;Wano et al, 1988;Bo¨hnlein et al, 1989;Nimer, 1991).…”