TANK-binding kinase 1 (TBK1) controls cell survival through PAI-2/serpinB2 and transglutaminase 2
TANK-binding kinase 1 (TBK1) controls cell survival through PAI-2/serpinB2 and transglutaminase 2
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DOI：
10.1073/pnas.1119296109
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发表时间：
2012-01-24
影响因子：
11.1
通讯作者：
Nakanishi, Makoto
中科院分区：
文献类型：
--
作者：
Delhase, Mireille;Kim, Soo-Youl;Nakanishi, Makoto
在暴露于肿瘤坏死因子的细胞中，生存和死亡之间的决定依赖于促凋亡和抗凋亡因子之间高度调控的平衡。肿瘤坏死因子激活的抗凋亡反应依赖于几种转录因子，包括核因子-kappa B及其RelA/p65亚基，这些转录因子通过I kappa B抑制剂的磷酸化降解而被激活，这一过程由I kappa B激酶复合体控制。在小鼠身上的遗传学研究已经确定I kappa B激酶相关的激酶坦克结合激酶1(TBK1；也被称为NAK或T2K)是一种额外的调节分子，可以促进肿瘤坏死因子下游的生存，但TBK1发挥其生存功能的机制仍然不清楚。在这里，我们证明了TBK1通过控制特定的RelA/p65磷酸化事件来触发抗凋亡反应。TBK1诱导的relA磷酸化导致纤溶酶原激活物抑制物-2(PAI-2)的诱导表达，PAI-2是丝氨酸蛋白家族的成员，具有已知的抗细胞凋亡活性。PAI-2通过稳定谷氨酰胺转氨酶2(TG2)来限制caspase-3的激活，转谷氨酰胺酶2可使原天冬氨酸氨基转移酶-3失活。重要的是，在两种肿瘤坏死因子依赖的急性肝损伤模型中，TG2(-/-)小鼠被发现更容易发生细胞凋亡。我们的结果证实了PAI-2和TG2是TBK1激活后触发的抗凋亡反应的下游介质。
The decision between survival and death in cells exposed to TNF relies on a highly regulated equilibrium between proapoptotic and antiapoptotic factors. The TNF-activated antiapoptotic response depends on several transcription factors, including NF-kappa B and its RelA/p65 subunit, that are activated through phosphorylation-mediated degradation of I kappa B inhibitors, a process controlled by the I kappa B kinase complex. Genetic studies in mice have identified the I kappa B kinase-related kinase TANK-binding kinase 1 (TBK1; also called NAK or T2K) as an additional regulatory molecule that promotes survival downstream of TNF, but the mechanism through which TBK1 exerts its survival function has remained elusive. Here we show that TBK1 triggers an antiapoptotic response by controlling a specific RelA/p65 phosphorylation event. TBK1-induced RelA phosphorylation results in inducible expression of plasminogen activator inhibitor-2 (PAI-2), a member of the serpin family with known antiapoptotic activity. PAI-2 limits caspase-3 activation through stabilization of transglutaminase 2 (TG2), which cross-links and inactivates procaspase-3. Importantly, Tg2(-/-) mice were found to be more susceptible to apoptotic cell death in two models of TNF-dependent acute liver injury. Our results establish PAI-2 and TG2 as downstream mediators in the antiapoptotic response triggered upon TBK1 activation.