Sokolova Olga, Kähne Thilo, Bryan Kenneth, Naumann Michael
Institute of Experimental Internal Medicine, Otto von Guericke University, Magdeburg 39120, Germany.
EMBL Australia Biomedical Informatics Group, Infection and Immunity Theme, South Australian Health and Medical Research Institute, Adelaide, South Australia 5000, Australia.
Oncotarget. 2018 Feb 21;9(18):14366-14381. doi: 10.18632/oncotarget.24544. eCollection 2018 Mar 6.
Transforming growth factor-β (TGFβ)-activated kinase 1 (TAK1) plays a central role in controlling the cellular pro-inflammatory response via the activation of the nuclear factor κB (NF-κB)- and mitogen-activated protein (MAP) kinases-dependent transcriptional programs. Here, we show that depletion of TAK1 and the TAK1-binding proteins TAB1 and TAB2 affects NF-κB, JNK and p38 phosphorylation and suppresses NF-κB activity in AGS cells infected with or stimulated with the cytokines TNF and IL-1β. To increase our understanding of TAK1 regulation and function, we performed mass spectrometry (MS)-based TAK1 interactomics. In addition to the identification of known and novel TAK1 interacting proteins, including TRIM28, CDC37 and STOML2, analysis of the MS data revealed various post-translational modifications within the TAK1/TAB complex. By applying siRNAs, TRIM28 and CDC37 were found to regulate phosphorylations of TAK1, IκB kinases IKKα/IKKβ and MAP kinases, NF-κB transactivation activity and IL-8 expression in the infected epithelial cells.
转化生长因子-β（TGFβ）激活激酶1（TAK1）通过激活核因子κB（NF-κB）和丝裂原活化蛋白（MAP）激酶依赖性转录程序，在控制细胞促炎反应中起核心作用。在此，我们表明，在感染或用细胞因子TNF和IL-1β刺激的AGS细胞中，TAK1以及TAK1结合蛋白TAB1和TAB2的缺失会影响NF-κB、JNK和p38的磷酸化，并抑制NF-κB活性。为了增进我们对TAK1调控和功能的理解，我们进行了基于质谱（MS）的TAK1相互作用组学研究。除了鉴定已知和新型的TAK1相互作用蛋白，包括TRIM28、CDC37和STOML2，对MS数据的分析还揭示了TAK1/TAB复合物中的各种翻译后修饰。通过应用小干扰RNA（siRNA），发现TRIM28和CDC37可调节感染上皮细胞中TAK1、IκB激酶IKKα/IKKβ和MAP激酶的磷酸化、NF-κB反式激活活性以及IL-8表达。
