The G-protein-coupled receptor kinase 5 inhibits NFκB transcriptional activity by inducing nuclear accumulation of IκBα
The G-protein-coupled receptor kinase 5 inhibits NFκB transcriptional activity by inducing nuclear accumulation of IκBα
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DOI：
10.1073/pnas.0804446105
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发表时间：
2008-11-18
影响因子：
11.1
通讯作者：
Iaccarino, Guido
中科院分区：
文献类型：
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作者：
Sorriento, Daniela;Ciccarelli, Michele;Iaccarino, Guido
G蛋白偶联受体(G蛋白偶联受体，GPCRK)被称为丝氨酸/苏氨酸激酶，调节GPCRs信号转导，但最近的研究表明，除了受体脱敏外，这些蛋白偶联受体还具有其他功能。事实上，GRK5可以通过核定位序列移位到核中，这表明该激酶调节核中的转录事件。为了评价GRK5-I kappabα相互作用对核因子kappaB信号的影响，我们在细胞培养中诱导了GRK5的过度表达和基因敲除。GRK5的过表达导致I kappa Bα的核积聚，导致核因子kappaB转录活性的抑制。而通过siRNA敲除GRK5则达到了相反的结果。GRK5和I kappa Bα之间的物理相互作用似乎是潜在的机制，而不是磷酸化事件。我们确定GRK5(RH)的基因蛋白信号同源调控域和I kappa Bα的IN末端结构域是参与这种相互作用的区域。为了证实这种对核因子kappa B的调控机制的生物学相关性，我们评估了GRK5-RH对依赖于核因子kappaB的表型的影响。尤其是，GRK5-RH的过表达在体外损害了细胞的凋亡保护和细胞因子的产生，在体内损害了炎症和组织再生。我们的结果揭示了GRK5在调节核因子kappaB转录活性中出人意料的作用。正确地看待这些发现，这一机制可能代表了所有这些涉及过量核因子kappaB活性的疾病的治疗靶点。
G-protein-coupled receptor (GPCR) kinases, GPCR, are known as serine/threonine kinases that regulate GPCR signaling, but recent findings propose functions for these kinases besides receptor desensitization. Indeed, GRK5 can translocate to the nucleus by means of a nuclear localization sequence, suggesting that this kinase regulates transcription events in the nucleus. To evaluate the effect of GRK5-I kappa b alpha interaction on NF kappa B signaling, we induced the overexpression and the knockdown of GRK5 in cell cultures. GRK5 overexpression causes nuclear accumulation of I kappa B alpha, leading to the inhibition of NF kappa B transcriptional activity. Opposite results are achieved by GRK5 knockdown through siRNA. A physical interaction between GRK5 and I kappa B alpha, rather than phosphorylative events, appears as the underlying mechanism. We identify the regulator of gene protein signaling homology domain of GRK5 (RH) and the IN-terminal domain Of I kappa B alpha as the regions involved in such interaction. To confirm the biological relevance of this mechanism of regulation for NF kappa B, we evaluated the effects of GRK5-RH on NF kappa B-dependent phenotypes. In particular, GRK5-RH overexpression impairs apoptosis protection and cytokine production in vitro and inflammation and tissue regeneration in vivo. Our results reveal an unexpected role for GRK5 in the regulation of NF kappa B transcription activity. Placing these findings in perspective, this mechanism may represent a therapeutic target for all those conditions involving excessive NF kappa B activity.