Negative regulation of NF-κB p65 activity by serine 536 phosphorylation.
Negative regulation of NF-κB p65 activity by serine 536 phosphorylation.
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DOI：
10.1126/scisignal.aab2820
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发表时间：
2016-08-23
影响因子：
7.3
通讯作者：
Schwabe RF
中科院分区：
文献类型：
--
作者：
Pradère JP;Hernandez C;Koppe C;Friedman RA;Luedde T;Schwabe RF
核因子κB（NF-κB）是炎症和细胞死亡的主要调节因子。尽管NF-κB的大部分活性是通过κ B（IκB）激酶（IKK）抑制剂依赖的IκB降解来调节的，但IKK也使NF-κB亚基磷酸化。在此，我们研究了人类NF-κ B亚基p65在IKK磷酸化位点丝氨酸536（Ser 536）处的磷酸化作用，这被认为是NF-κB活化和核转位所必需的。通过对表达突变型p65的小鼠（S534 A小鼠）进行实验，该突变型p65在第534位（人类Ser 536的小鼠同源物）处具有丙氨酸到丝氨酸的取代，我们观察到在向小鼠注射炎性刺激物脂多糖（LPS）或暴露于γ射线后，NF-κ B依赖性基因的表达增加，并且增强的基因表达在较晚的时间点最明显。与野生型小鼠相比，S534 A小鼠在注射LPS后显示出增加的死亡率。S534 A小鼠中增加的NF-κ B信号传导至少部分由S534 A p65蛋白与Ser 534磷酸化野生型蛋白相比增加的稳定性解释。总之，我们的研究结果表明，小鼠p65的Ser 534磷酸化（以及人p65的Ser 536磷酸化）不是其核转位所必需的，而是抑制NF-κ B信号传导以防止有害的炎症。
Nuclear factor κB (NF-κB) is a master regulator of inflammation and cell death. Whereas most of the activity of NF-κB is regulated through the inhibitor of kB (IκB) kinase (IKK)–dependent degradation of IκB, IKK also phosphorylates subunits of NF-κB. Here, we investigated the contribution of the phosphorylation of the NF-κ B subunit p65 at the IKK phosphorylation site serine 536 (Ser536) in humans, which is thought to be required for the activation and nuclear translocation of NF-κB. Through experiments with knock-in mice (S534A mice) expressing a mutant p65 with an alanine-to-serine substitution at position 534 (the murine homolog of human Ser536), we observed increased expression of NF-κ B–dependent genes after injection of mice with the inflammatory stimulus lipopolysaccharide (LPS) or exposure to gamma irradiation, and the enhanced gene expression was most pronounced at late time points. Compared to wild-type mice, S534A mice displayed increased mortality after injection with LPS. Increased NF-κ B signaling in the S534A mice was at least in part explained by the increased stability of the S534A p65 protein compared to that of the Ser534-phosphorylated wild-type protein. Together, our results suggest that Ser534 phosphorylation of p65 in mice (and, by extension, Ser536 phosphorylation of human p65) is not required for its nuclear translocation, but instead inhibits NF-κ B signaling to prevent deleterious inflammation.