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首页> 外文期刊>Molecular and Cellular Biology >CD28 mediates a potent costimulatory signal for rapid degradation of IkappaBbeta which is associated with accelerated activation of various NF-kappaB/Rel heterodimers.
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CD28 mediates a potent costimulatory signal for rapid degradation of IkappaBbeta which is associated with accelerated activation of various NF-kappaB/Rel heterodimers.

机译：CD28介导了IkappaBbeta快速降解的有效共刺激信号，该信号与各种NF-kappaB / Rel异二聚体的加速活化有关。

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Optimal activation of T cells requires at least two signals delivered by the T-cell receptor complex and costimulatory molecules such as CD28. The CD28 signaling participates in the transcription of the interleukin-2 gene through activation of an enhancer termed the CD28-responsive element (CD28RE). Stimulation of CD28 enhances mitogen-mediated induction of CD28RE-binding proteins including members of the NF-kappaB/Rel transcription factor family, although the underlying mechanism remains elusive. In this report, we show that CD28 costimulation leads to biphasic induction of NF-kappaB/Rel heterodimers, including early-phase induction of p50/RelA and c-Rel/RelA and late-phase induction of p50/c-Rel. Interestingly, activation of these NF-kappaB/Rel complexes by the CD28 signal is associated with the rapid degradation of both IkappaBalpha and IkappaBbeta, two major cytoplasmic inhibitors of NF-kappaB/Rel. Although IkappaBalpha degradation can be induced by phorbol ester alone, degradation of IkappaBbeta is largely dependent on the CD28 costimulatory signal. We further demonstrate that CD28-mediated transactivation of the CD28RE enhancer is potently inhibited by an N-terminal truncation mutant of IkappaBbeta that is incapable of responding to the degradation signals. Together, these results suggest that the CD28 costimulatory signal augments activation of NF-kappaB/Rel by promoting degradation of IkappaBbeta as well as enhancing degradation of IkappaBalpha and that induction of NF-kappaB/Rel serves as an essential step in the signal-mediated activation of the CD28RE enhancer.
机译：T细胞的最佳激活需要至少两个由T细胞受体复合物和共刺激分子（例如CD28）传递的信号。 CD28信号传导通过激活称为CD28应答元件（CD28RE）的增强子参与白介素2基因的转录。尽管潜在的机制仍然难以捉摸，但刺激CD28增强了丝裂原介导的CD28RE结合蛋白（包括NF-κB/ Rel转录因子家族成员）的诱导。在此报告中，我们显示CD28共刺激可导致NF-κB/ Rel异二聚体的双相诱导，包括p50 / RelA和c-Rel / RelA的早期诱导和p50 / c-Rel的后期诱导。有趣的是，通过CD28信号激活这些NF-kappaB / Rel复合物与NF-kappaB / Rel的两种主要细胞质抑制剂IkappaBalpha和IkappaBbeta的快速降解有关。尽管IkappaBalpha的降解可以单独由佛波酯诱导，但IkappaBbeta的降解在很大程度上取决于CD28共刺激信号。我们进一步证明，CD28RE增强子的CD28介导的反式激活被IkappaBbeta的N端截短突变体有效抑制，该突变体无法响应降解信号。总之，这些结果表明，CD28共刺激信号通过促进IkappaBbeta的降解以及增强IkappaBalpha的降解来增强NF-kappaB / Rel的激活，并且NF-kappaB / Rel的诱导是信号介导的激活中的重要步骤CD28RE增强剂。

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