McKinsey T A, Brockman J A, Scherer D C, Al-Murrani S W, Green P L, Ballard D W
Howard Hughes Medical Institute, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
Mol Cell Biol. 1996 May;16(5):2083-90. doi: 10.1128/MCB.16.5.2083.
In resting T lymphocytes, the transcription factor NF-kappaB is sequestered in the cytoplasm via interactions with members of the I kappa B family of inhibitors, including IkappaBalpha and IkappaBbeta. During normal T-cell activation, IkappaBalpha is rapidly phosphorylated, ubiquitinated, and degraded by the 26S proteasome, thus permitting the release of functional NF-kappaB. In contrast to its transient pattern of nuclear induction during an immune response, NF-kappaB is constitutively activated in cells expressing the Tax transforming protein of human T-cell leukemia virus type I (HTLV-1). Recent studies indicate that HTLV-1 Tax targets IkappaBalpha to the ubiquitin-proteasome pathway. However, it remains unclear how this viral protein induces a persistent rather than transient NF-kappaB response. In this report, we provide evidence that in addition to acting on IkappaBalpha, Tax stimulates the turnover Of IkappaBbeta via a related targeting mechanism. Like IkappaBalpha, Tax-mediated breakdown of IkappaBbeta in transfected T lymphocytes is blocked either by cell-permeable proteasome inhibitors or by mutation Of IkappaBbeta at two serine residues present within its N-terminal region. Despite the dual specificity of HTLV-1 Tax for IkappaBalpha and IkappaBbeta at the protein level, Tax selectively stimulates NF-kappaB-directed transcription of the IkappaBalpha gene. Consequently, IkappaBbeta protein expression is chronically downregulated in HTLV-1-infected T lymphocytes. These findings with IkappaBbeta provide a potential mechanism for the constitutive activation of NF-kappaB in Tax-expressing cells.
在静息的T淋巴细胞中，转录因子NF-κB通过与IκB家族抑制因子（包括IκBα和IκBβ）成员相互作用而被隔离在细胞质中。在正常T细胞激活过程中，IκBα迅速被磷酸化、泛素化，并被26S蛋白酶体降解，从而使功能性NF-κB得以释放。与免疫反应期间其短暂的核诱导模式不同，NF-κB在表达人T细胞白血病病毒I型（HTLV-1）Tax转化蛋白的细胞中持续激活。最近的研究表明，HTLV-1 Tax将IκBα靶向泛素-蛋白酶体途径。然而，尚不清楚这种病毒蛋白如何诱导持续性而非短暂性的NF-κB反应。在本报告中，我们提供证据表明，除作用于IκBα外，Tax还通过相关靶向机制刺激IκBβ的周转。与IκBα一样，Tax介导的转染T淋巴细胞中IκBβ的降解可被细胞渗透性蛋白酶体抑制剂或IκBβ N端区域两个丝氨酸残基的突变所阻断。尽管HTLV-1 Tax在蛋白质水平上对IκBα和IκBβ具有双重特异性，但Tax选择性地刺激IκBα基因的NF-κB定向转录。因此，在HTLV-1感染的T淋巴细胞中，IκBβ蛋白表达长期下调。这些关于IκBβ的发现为Tax表达细胞中NF-κB的组成性激活提供了一种潜在机制。
