NLK在炎症反应、抗病毒应答和肿瘤发生中的作用及机制研究
摘要
1.NLK在TNFα诱导的NF-κB信号转导中的作用
转录因子NF-κB广泛存在于各种细胞中,它调节了细胞的应激反应,炎症应答相关基因的转录。它的失调会引起许多疾病,如类风湿性关节炎,因此严格调控NF-κB的激活对于细胞维持压力应答和炎症稳态非常重要。近年来尽管不断揭示NF-κB激活的机制,然而在TNFα诱导的NF-κB信号转导中,IKKβ激酶活性失活的机制还不清楚。在这里我们报道了NLK通过抑制IKKβ的磷酸化负调节了TNFα诱导的NF-κB信号转导。过表达NLK极大的降低了TNFα诱导的NF-κB的激活,IκBα的降解和p65的细胞核转位;然而NLK缺失却导致了相反的结果。从机制上来说,我们确定了NLK和IKK复合物相互作用,该相互作用抑制了TAK1/IKKβ复合物的组装,并且减少了IκB激酶的磷酸化。我们的结果表明NLK可以干扰TAK1和IKKβ的相互作用,导致蛋白激酶IKKβ失活,最终负调节TNFα诱导的NF-κB激活,这促进了对NF-κB失活机制的理解。
2.NLK在细胞抗病毒应答中的作用
RLR能够检测细胞质中病毒RNA并且激活线粒体抗病毒接头蛋白MAVS和TRAF3,从而导致Ⅰ型干扰素的快速产生并起始天然免疫抗病毒应答。尽管TRAF3对于细胞的抗病毒应答非常重要,但是对于调节它的分子机制到目前还知之甚少。我们的研究结果表明NLK通过调节TRAF3的泛素化抑制了病毒诱导的IFN-β产生和抗病毒免疫应答。过表达NLK抑制了病毒诱导的IFN-β启动子激活和抗病毒细胞因子的产生；而NLK缺失则促进了抗病毒细胞因子的产生从而抑制了病毒对细胞的感染,这些现象在引入NLK之后很大程度上得到恢复。进一步研究发现NLK能与TRAF3相互作用并且磷酸化TRAF3,磷酸化的TRAF3可以抑制它的泛素化和随后的TBK1和IRF3激活。持续性磷酸化的TRAF3突变体也有类似的效果,它能够抑制病毒诱导的IFN-β启动子的激活,TRAF3K63连接的泛素化和IFN-β的产生。这些发现揭示了NLK蛋白的新功能,它通过调节TRAF3的泛素化参与了Ⅰ型干扰素信号转导,这对于进一步了解NLK的功能和理解TRAF3在细胞抗病毒应答中的调节机制起着很重要的作用。
3.NLK在大肠癌发生中的作用研究
在真核生物中,细胞周期检验点对于细胞周期循环,细胞增殖和肿瘤发生具有很重要的作用。在这里,我们报道了NLK作为一个重要的癌基因参与大肠癌形成。使用同源重组方法在HCT116细胞中敲除NLK,通过集落形成,生长曲线,软琼脂和裸鼠异种移植实验分析该细胞,结果表明不论在体内还是体外NLK缺失都极大的抑制了肿瘤形成。在NLK缺失的细胞中,我们发现了明显的细胞周期的改变,NLK的缺失会增加G1期细胞比例并且G2/M期的比例会相应减少。缺少NLK的细胞,cyclinD3的蛋白水平明显减少,而且Rb蛋白磷酸化水平也有非常明显降低。HDACl和Rb通过形成一个复合物来控制G1/S细胞周期检验点,而NLK能够和HDACl相互作用,这说明NLK可能调节了这个复合物来调节细胞周期。这些结果都说明了NLK可能通过影响Rb复合物和cyclinD3的蛋白水平来控制G1/S细胞周期检验点,从而调节细胞周期循环进程。总的来说这些结果表明了NLK是一个有前景的大肠癌药物靶标。
1. Roles of NLK in TNFa-induced NF-κB signaling
Stringent negative regulation of the transcription factor NF-κB is essential for maintaining cellular stress responses and homeostasis. However, the tight regulation mechanisms of IKKβ are still not clear. Here, we reported that the nemo-like kinase (NLK) is a suppressor of tumor necrosis factor (TNFα)-induced NF-κB signaling by inhibiting the phosphorylation of IKKβ. Overexpression of NLK largely blocked TNFa-induced NF-κB activation, p65nuclear localization and IκBαdegradation; whereas genetic inactivation of NLK showed opposing results. Mechanistically, we identified that NLK interacted with IκB kinase (IKK)-associated complex, which in turn inhibited the assembly of the TAK1/IKKβ and thereby, diminished the IκB kinase phosphorylation. Our results indicate that NLK functions as a pivotal negative regulator in TNFa-induced activation of NF-κB via disrupting the interaction of TAK1with IKKβ.
2. Function of NLK in cellular antiviral response
Detection of viral acid by the RIG-like helicase (RLH) family of intracellular receptors activates the mitochondrial antiviral signaling adaptor MAVS and TRAF3, which leads to the rapid production of type I IFN and initiates innate antiviral immune response. Although TRAF3is vital to antiviral immunity, the molecular mechanisms responsible for its tight regulation are still poorly understood. Here, we show that the Nemo-like Kinase (NLK) inhibits IFN-β induction and antiviral immune response during a viral infection by regulating ubiquitination of TRAF3. Expression of NLK results in the potent inhibition of virus-induced IFN-β promoter activity and antiviral cytokines production. Depletion of NLK using AAV-mediated homologous recombination promotes virus-induced antiviral cytokines production and decreases the viral replication, which potent rescue by reintroduction NLK. Moreover, NLK interacts with TRAF3and phosphorylates it, which in turn leads to inhibition of ubiquitination of TRAF3and subsequent activation of TBK1and IRF3. We further found that mimics phosphorylation of TRAF3has the similar effects for inhibition of virus-induced IFN-β production. These findings identify an unrecognized role for NLK in the regulation of type I interferon signaling and provide direct insight into the molecular mechanisms which NLK regulates ubiquitination of TRAF3for influence on its activation.
3. Roles of NLK in the colorectal carcinogenesis
The cell cycle checkpoints are essential for cell proliferation, cell cycle and tumorigenesis in all eukaryotes. Herein, we report that NLK as a pivotal oncongene involves in the tumorigenesis. Completely depletion of NLK using knock-out rather than down-regulation hindered tumorigenesis both in vitro and in vivo, as assessed via colony formation, growth curve, soft agar and xenograft assays. In the NLK-deficient cells, we find the observed cell cycle changes, which have increased G1phase and decreased G2/M phase. In the NLK-deficient cells, the protein level of cyclinD3is potently decreased. We also have observed the reduced phosphorylation of Rb. NLK also associated with HDAC1, which form a complex with Rb to control G1/S cell cycle checkpoint. These results suggest that NLK control the G1/S cell cycle checkpoint by impacting protein level of cyclinD3and Rb complex. Collectively, these results suggest that NLK is a promising drug target for the treatment of colorectal cancer.
转录因子NF-κB广泛存在于各种细胞中,它调节了细胞的应激反应,炎症应答相关基因的转录。它的失调会引起许多疾病,如类风湿性关节炎,因此严格调控NF-κB的激活对于细胞维持压力应答和炎症稳态非常重要。近年来尽管不断揭示NF-κB激活的机制,然而在TNFα诱导的NF-κB信号转导中,IKKβ激酶活性失活的机制还不清楚。在这里我们报道了NLK通过抑制IKKβ的磷酸化负调节了TNFα诱导的NF-κB信号转导。过表达NLK极大的降低了TNFα诱导的NF-κB的激活,IκBα的降解和p65的细胞核转位;然而NLK缺失却导致了相反的结果。从机制上来说,我们确定了NLK和IKK复合物相互作用,该相互作用抑制了TAK1/IKKβ复合物的组装,并且减少了IκB激酶的磷酸化。我们的结果表明NLK可以干扰TAK1和IKKβ的相互作用,导致蛋白激酶IKKβ失活,最终负调节TNFα诱导的NF-κB激活,这促进了对NF-κB失活机制的理解。
2.NLK在细胞抗病毒应答中的作用
RLR能够检测细胞质中病毒RNA并且激活线粒体抗病毒接头蛋白MAVS和TRAF3,从而导致Ⅰ型干扰素的快速产生并起始天然免疫抗病毒应答。尽管TRAF3对于细胞的抗病毒应答非常重要,但是对于调节它的分子机制到目前还知之甚少。我们的研究结果表明NLK通过调节TRAF3的泛素化抑制了病毒诱导的IFN-β产生和抗病毒免疫应答。过表达NLK抑制了病毒诱导的IFN-β启动子激活和抗病毒细胞因子的产生；而NLK缺失则促进了抗病毒细胞因子的产生从而抑制了病毒对细胞的感染,这些现象在引入NLK之后很大程度上得到恢复。进一步研究发现NLK能与TRAF3相互作用并且磷酸化TRAF3,磷酸化的TRAF3可以抑制它的泛素化和随后的TBK1和IRF3激活。持续性磷酸化的TRAF3突变体也有类似的效果,它能够抑制病毒诱导的IFN-β启动子的激活,TRAF3K63连接的泛素化和IFN-β的产生。这些发现揭示了NLK蛋白的新功能,它通过调节TRAF3的泛素化参与了Ⅰ型干扰素信号转导,这对于进一步了解NLK的功能和理解TRAF3在细胞抗病毒应答中的调节机制起着很重要的作用。
3.NLK在大肠癌发生中的作用研究
在真核生物中,细胞周期检验点对于细胞周期循环,细胞增殖和肿瘤发生具有很重要的作用。在这里,我们报道了NLK作为一个重要的癌基因参与大肠癌形成。使用同源重组方法在HCT116细胞中敲除NLK,通过集落形成,生长曲线,软琼脂和裸鼠异种移植实验分析该细胞,结果表明不论在体内还是体外NLK缺失都极大的抑制了肿瘤形成。在NLK缺失的细胞中,我们发现了明显的细胞周期的改变,NLK的缺失会增加G1期细胞比例并且G2/M期的比例会相应减少。缺少NLK的细胞,cyclinD3的蛋白水平明显减少,而且Rb蛋白磷酸化水平也有非常明显降低。HDACl和Rb通过形成一个复合物来控制G1/S细胞周期检验点,而NLK能够和HDACl相互作用,这说明NLK可能调节了这个复合物来调节细胞周期。这些结果都说明了NLK可能通过影响Rb复合物和cyclinD3的蛋白水平来控制G1/S细胞周期检验点,从而调节细胞周期循环进程。总的来说这些结果表明了NLK是一个有前景的大肠癌药物靶标。
1. Roles of NLK in TNFa-induced NF-κB signaling
Stringent negative regulation of the transcription factor NF-κB is essential for maintaining cellular stress responses and homeostasis. However, the tight regulation mechanisms of IKKβ are still not clear. Here, we reported that the nemo-like kinase (NLK) is a suppressor of tumor necrosis factor (TNFα)-induced NF-κB signaling by inhibiting the phosphorylation of IKKβ. Overexpression of NLK largely blocked TNFa-induced NF-κB activation, p65nuclear localization and IκBαdegradation; whereas genetic inactivation of NLK showed opposing results. Mechanistically, we identified that NLK interacted with IκB kinase (IKK)-associated complex, which in turn inhibited the assembly of the TAK1/IKKβ and thereby, diminished the IκB kinase phosphorylation. Our results indicate that NLK functions as a pivotal negative regulator in TNFa-induced activation of NF-κB via disrupting the interaction of TAK1with IKKβ.
2. Function of NLK in cellular antiviral response
Detection of viral acid by the RIG-like helicase (RLH) family of intracellular receptors activates the mitochondrial antiviral signaling adaptor MAVS and TRAF3, which leads to the rapid production of type I IFN and initiates innate antiviral immune response. Although TRAF3is vital to antiviral immunity, the molecular mechanisms responsible for its tight regulation are still poorly understood. Here, we show that the Nemo-like Kinase (NLK) inhibits IFN-β induction and antiviral immune response during a viral infection by regulating ubiquitination of TRAF3. Expression of NLK results in the potent inhibition of virus-induced IFN-β promoter activity and antiviral cytokines production. Depletion of NLK using AAV-mediated homologous recombination promotes virus-induced antiviral cytokines production and decreases the viral replication, which potent rescue by reintroduction NLK. Moreover, NLK interacts with TRAF3and phosphorylates it, which in turn leads to inhibition of ubiquitination of TRAF3and subsequent activation of TBK1and IRF3. We further found that mimics phosphorylation of TRAF3has the similar effects for inhibition of virus-induced IFN-β production. These findings identify an unrecognized role for NLK in the regulation of type I interferon signaling and provide direct insight into the molecular mechanisms which NLK regulates ubiquitination of TRAF3for influence on its activation.
3. Roles of NLK in the colorectal carcinogenesis
The cell cycle checkpoints are essential for cell proliferation, cell cycle and tumorigenesis in all eukaryotes. Herein, we report that NLK as a pivotal oncongene involves in the tumorigenesis. Completely depletion of NLK using knock-out rather than down-regulation hindered tumorigenesis both in vitro and in vivo, as assessed via colony formation, growth curve, soft agar and xenograft assays. In the NLK-deficient cells, we find the observed cell cycle changes, which have increased G1phase and decreased G2/M phase. In the NLK-deficient cells, the protein level of cyclinD3is potently decreased. We also have observed the reduced phosphorylation of Rb. NLK also associated with HDAC1, which form a complex with Rb to control G1/S cell cycle checkpoint. These results suggest that NLK control the G1/S cell cycle checkpoint by impacting protein level of cyclinD3and Rb complex. Collectively, these results suggest that NLK is a promising drug target for the treatment of colorectal cancer.
引文
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