Yang Fan, Tang Eric, Guan Kunliang, Wang Cun-Yu
Laboratory of Molecular Signaling and Apoptosis, Department of Biologic and Materials Sciences, University of Michigan, Ann Arbor, MI 48109, USA.
J Immunol. 2003 Jun 1;170(11):5630-5. doi: 10.4049/jimmunol.170.11.5630.
Activation of the I kappa B kinase (IKK) complex by LPS induces phosphorylation and degradation of I kappa B alpha, leading to the nuclear translocation of NF-kappa B. Although it is essential for NF-kappa B activation, emerging evidence has indicated that the nuclear translocation of NF-kappa B is not sufficient to activate NF-kappa B-dependent transcription. Here, we reported that LPS induced the phosphorylation of the p65 trans-activation domain on serine 536 in monocytes/macrophages. Using mouse embryonic fibroblasts lacking either IKK alpha or IKK beta, we found that IKK beta played an essential role in LPS-induced p65 phosphorylation on serine 536, while IKK alpha was partially required for the p65 phosphorylation. The LPS-induced p65 phosphorylation on serine 536 was independent of the phosphatidylinositol 3'-kinase/Akt signaling pathway. Furthermore, we found that the phosphorylation on serine 536 increased the p65 transcription activity. In summary, our results demonstrate that IKK beta plays an essential role in the LPS-induced p65 phosphorylation on serine 536, which may represent a mechanism to regulate the NF-kappa B transcription activity by LPS.
脂多糖（LPS）激活IκB激酶（IKK）复合物可诱导IκBα的磷酸化和降解，导致NF-κB的核转位。尽管这对NF-κB激活至关重要，但新出现的证据表明，NF-κB的核转位不足以激活NF-κB依赖性转录。在此，我们报道LPS可诱导单核细胞/巨噬细胞中p65反式激活结构域丝氨酸536位点的磷酸化。利用缺乏IKKα或IKKβ的小鼠胚胎成纤维细胞，我们发现IKKβ在LPS诱导的丝氨酸536位点p65磷酸化中起关键作用，而IKKα对p65磷酸化是部分必需的。LPS诱导的丝氨酸536位点p65磷酸化独立于磷脂酰肌醇3'-激酶/Akt信号通路。此外，我们发现丝氨酸536位点的磷酸化增加了p65的转录活性。总之，我们的结果表明IKKβ在LPS诱导的丝氨酸536位点p65磷酸化中起关键作用，这可能是LPS调节NF-κB转录活性的一种机制。
