Meng Jie, Jiang Jing-Jing, Atsumi Toru, Bando Hidenori, Okuyama Yuko, Sabharwal Lavannya, Nakagawa Ikuma, Higuchi Haruka, Ota Mitsutoshi, Okawara Momoko, Ishitani Ryuichiro, Nureki Osamu, Higo Daisuke, Arima Yasunobu, Ogura Hideki, Kamimura Daisuke, Murakami Masaaki
Division of Molecular Neuroimmunology, Institute for Genetic Medicine and Graduate School of Medicine, Hokkaido University, Sapporo 080-0615, Japan.
Laboratory of Developmental Immunology, Graduate School of Frontier Biosciences, Graduate School of Medicine, and World Premier International Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan.
J Immunol. 2016 Oct 15;197(8):3111-3119. doi: 10.4049/jimmunol.1601082. Epub 2016 Sep 14.
The breakpoint cluster region (BCR) is known as a kinase and cause of leukemia upon fusing to Abl kinase. In this study, we demonstrate that BCR associated with the α subunit of casein kinase II (CK2α), rather than BCR itself, is required for inflammation development. We found that BCR knockdown inhibited NF-κB activation in vitro and in vivo. Computer simulation, however, suggested that the putative BCR kinase domain has an unstable structure with minimal enzymatic activity. Liquid chromatography-tandem mass spectrometry analysis showed that CK2α associated with BCR. We found the BCR functions are mediated by CK2α. Indeed, CK2α associated with adaptor molecules of TNF-αR and phosphorylated BCR at Y177 to establish a p65 binding site after TNF-α stimulation. Notably, p65 S529 phosphorylation by CK2α creates a p300 binding site and increased p65-mediated transcription followed by inflammation development in vivo. These results suggest that BCR-mediated inflammation is dependent on CK2α, and the BCR-CK2α complex could be a novel therapeutic target for various inflammatory diseases.
断裂点簇集区（BCR）是一种激酶，与Abl激酶融合后可引发白血病。在本研究中，我们证明炎症发展需要与酪蛋白激酶IIα亚基（CK2α）相关联的BCR，而非BCR本身。我们发现BCR敲低在体外和体内均抑制NF-κB激活。然而，计算机模拟表明，假定的BCR激酶结构域具有不稳定结构且酶活性极低。液相色谱-串联质谱分析表明CK2α与BCR相关联。我们发现BCR的功能由CK2α介导。实际上，CK2α与TNF-αR的衔接分子相关联，并在TNF-α刺激后使BCR的Y177位点磷酸化，从而建立一个p65结合位点。值得注意的是，CK2α介导的p65 S529磷酸化产生一个p300结合位点，并在体内炎症发展后增加p65介导的转录。这些结果表明，BCR介导的炎症依赖于CK2α，并且BCR-CK2α复合物可能是各种炎症性疾病的新型治疗靶点。
