NF-κB c-Rel Dictates the Inflammatory Threshold by Acting as a Transcriptional Repressor
NF-κB c-Rel Dictates the Inflammatory Threshold by Acting as a Transcriptional Repressor
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DOI：
10.1016/j.isci.2020.100876
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发表时间：
2020-03-27
期刊：
影响因子：
5.8
通讯作者：
Ramakrishnan, Parameswaran
中科院分区：
文献类型：
--
作者：
de Jesus, Tristan James;Ramakrishnan, Parameswaran
核因子-kappaB/Rel转录因子家族在炎症反应的启动和消退中发挥核心作用。在这里，我们确定了核因子-kappa B亚单位c-rel的一个功能，作为炎症基因的转录抑制因子。C-Rel的基因缺失显著增强了几种由肿瘤坏死因子-α诱导的依赖RelA的炎症介质的表达。V-Rel是c-Rel的病毒同源物，但不是RelB，也具有这种抑制功能。在机制上，我们发现c-Rel选择性地与共抑制物HDAC1结合，并竞争性地与介导HDAC1向炎症基因启动子募集的DNA结合。C-Rel DNA结合区酪氨酸(25)处的特异点突变，在人类中存在错义单核苷酸变异(Y25H)，完全丧失了其结合DNA的能力，并抑制了肿瘤坏死因子-α诱导的RELA介导的转录。我们的研究结果表明，反式激活因子NF-kappa B亚单位c-rel在维持炎症内稳态中也发挥了转录抑制因子的作用。
NF-kappa B/Rel family of transcription factors plays a central role in initiation and resolution of inflammatory responses. Here, we identified a function of the NF-kappa B subunit c-Rel as a transcriptional repressor of inflammatory genes. Genetic deletion of c-Rel substantially potentiates the expression of several TNF-alpha-induced RelA-dependent mediators of inflammation. v-Rel, the viral homologue of c-Rel, but not RelB, also possesses this repressive function. Mechanistically, we found that c-Rel selectively binds to the co-repressor HDAC1 and competitively binds to the DNA mediating HDAC1 recruitment to the promoters of inflammatory genes. A specific point mutation at tyrosine(25) in c-Rel's DNA-binding domain, for which a missense single nucleotide variation (Y25H) exists in humans, completely abrogated its ability to bind DNA and repress TNF-alpha-induced, RelA-mediated transcription. Our findings reveal that the transactivator NF-kappa B subunit c-Rel also plays a role as a transcriptional repressor in the maintenance of inflammatory homeostasis.