A novel mechanism of control of NFκB activation and inflammation involving A2B adenosine receptors
A novel mechanism of control of NFκB activation and inflammation involving A2B adenosine receptors
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DOI：
10.1242/jcs.105023
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发表时间：
2012-10-01
影响因子：
4
通讯作者：
Huang, Pingbo
中科院分区：
文献类型：
--
作者：
Sun, Ying;Duan, Yuanyuan;Huang, Pingbo
核因子-kappa-B(NF-kappa-B)途径控制着包括炎症在内的多种过程，因此，对核因子-kappaB的调控一直是研究的重点。在这里，我们报告了一个新发现的对这一途径的调节，涉及转录因子NF kappa B1(NF kappa B的p105亚单位)与A(2B)腺苷受体(A(2B)AR)的C末端的直接结合，而不依赖于配体的激活。有趣的是，A(2B)AR与p105上的特定位点结合阻止了p105蛋白的多泛素化和降解。在A(2B)AR基因敲除小鼠的细胞中，异位表达的A(2B)AR增加了p105水平并抑制了核因子kappaB的激活，而p105蛋白水平则降低了。根据已知p105对抗炎和促炎细胞因子表达的调节，A(2B)AR基因缺失的小鼠产生较少的IL-10，而产生更多的IL-12和肿瘤坏死因子(TNF-α)。综上所述，我们的结果表明，A(2B)AR通过与p105物理相互作用来抑制核因子kappaB的激活，从而阻止其多泛素化和降解。我们的发现揭示了A(2B)AR令人惊讶的功能，并提供了一种新的机制来控制核因子kappa B途径和炎症。
The nuclear factor kappa B (NF kappa B) pathway controls a variety of processes, including inflammation, and thus, the regulation of NF kappa B has been a continued focus of study. Here, we report a newly identified regulation of this pathway, involving direct binding of the transcription factor NF kappa B1 (the p105 subunit of NF kappa B) to the C-terminus of the A(2B) adenosine receptor (A(2B)AR), independent of ligand activation. Intriguingly, binding of A(2B)AR to specific sites on p105 prevents polyubiquitylation and degradation of p105 protein. Ectopic expression of the A(2B)AR increases p105 levels and inhibits NF kappa B activation, whereas p105 protein levels are reduced in cells from A(2B)AR-knockout mice. In accordance with the known regulation of expression of anti- and pro-inflammatory cytokines by p105, A(2B)AR-null mice generate less interleukin (IL)-10, and more IL-12 and tumor necrosis factor (TNF-alpha). Taken together, our results show that the A(2B)AR inhibits NF kappa B activation by physically interacting with p105, thereby blocking its polyubiquitylation and degradation. Our findings unveil a surprising function for the A(2B)AR, and provide a novel mechanistic insight into the control of the NF kappa B pathway and inflammation.