Béraud C, Greene W C
Gladstone Institute of Virology and Immunology, San Francisco, California, USA.
J Acquir Immune Defic Syndr Hum Retrovirol. 1996;13 Suppl 1:S76-84. doi: 10.1097/00042560-199600001-00014.
The human T-cell leukemia virus type I (HTLV-I) has been etiologically associated with the development of the adult T-cell leukemia (ATL) as well as degenerative neurologic syndrome termed tropical spastic paraparesis (TSP). HTLV-I encodes a potent transactivator protein termed Tax that appears to play an important role in the process of T-cell immortalization. Even though the mechanisms by which Tax induces transformation are still unknown, it seems likely that the ability of Tax to alter the expression of many cellular genes plays an important part in this process. Tax does not bind directly to DNA but rather deregulates the activity of cellular transcription factors. One family of host transcription factors whose activity is altered by Tax includes NF-kappa B/Rel. These transcription factors are post-transcriptionally regulated by their assembly with a second family of inhibitory proteins termed I kappa B that serve to sequester the NF-kappa B/Rel complexes in the cytoplasm. Upon cellular activation, I kappa B alpha is phosphorylated, polyubiquitinated, and degraded in the proteasome. This proteolytic event liberates NF-kappa B, permitting its rapid translocation into the nucleus where it binds to its cognate enhancer elements. Similarly, the p105 precursor of the NF-kappa B p50 subunit is also post-translationally processed in the proteasome. The mechanisms by which Tax activates NF-kappa B remain unclear, and findings presented in the literature are often controversial. We identified a physical interaction between Tax and the HsN3 subunit of the human proteasome. This raises the intriguing possibility that physical association of the HsN3 proteasome subunit with HTLV-I Tax coupled with the independent interaction of Tax with either p100 or p65-I kappa B alpha targets these cytoplasmic NF-kappa B/Rel complexes to the proteasome for processing.
人类I型T细胞白血病病毒（HTLV-I）在病因上与成人T细胞白血病（ATL）的发生以及称为热带痉挛性截瘫（TSP）的退行性神经综合征相关。HTLV-I编码一种名为Tax的强效反式激活蛋白，该蛋白似乎在T细胞永生化过程中起重要作用。尽管Tax诱导转化的机制尚不清楚，但Tax改变许多细胞基因表达的能力似乎在这一过程中起重要作用。Tax不直接与DNA结合，而是解除细胞转录因子的活性。其活性被Tax改变的一类宿主转录因子包括NF-κB/Rel。这些转录因子通过与第二类抑制蛋白（称为IκB）组装进行转录后调控，IκB用于将NF-κB/Rel复合物隔离在细胞质中。细胞激活后，IκBα被磷酸化、多聚泛素化，并在蛋白酶体中降解。这一蛋白水解事件释放出NF-κB，使其迅速转运到细胞核中，在那里它与同源增强子元件结合。同样，NF-κB p50亚基的p105前体也在蛋白酶体中进行翻译后加工。Tax激活NF-κB的机制仍不清楚，文献中的研究结果往往存在争议。我们发现Tax与人蛋白酶体的HsN3亚基之间存在物理相互作用。这就提出了一种有趣的可能性，即HsN3蛋白酶体亚基与HTLV-I Tax的物理结合，再加上Tax与p100或p65-IκBα的独立相互作用，将这些细胞质中的NF-κB/Rel复合物靶向蛋白酶体进行加工。
