Noncanonical cell death program independent of caspase activation cascade and necroptotic modules is elicited by loss of TGFβ-activated kinase 1.
Noncanonical cell death program independent of caspase activation cascade and necroptotic modules is elicited by loss of TGFβ-activated kinase 1.
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DOI：
10.1038/s41598-017-03112-1
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发表时间：
2017-06-07
影响因子：
4.6
通讯作者：
Morioka S
中科院分区：
文献类型：
--
作者：
Mihaly SR;Sakamachi Y;Ninomiya-Tsuji J;Morioka S
程序性细胞死亡（PCD）以多种形式发生，包括凋亡和坏死性凋亡。细胞凋亡是通过激活半胱天冬酶来实现的，而坏死性凋亡则依赖于受体相互作用蛋白激酶3（RIPK3）。细胞死亡的精确控制对于组织稳态是至关重要的。事实上，坏死性凋亡是由半胱天冬酶抑制引发的，以确保细胞死亡。在这里，我们确定了一个以前未知的细胞死亡途径TAK1调节，这是出乎意料地挑起抑制caspase活性和坏死性凋亡级联。TAK1的消融触发巨噬细胞的自发性死亡。同时抑制半胱天冬酶和RIPK3不能完全恢复细胞活力。先前的研究表明，成纤维细胞中TAK1的缺失导致TNF诱导的细胞凋亡，并且半胱天冬酶的额外抑制导致坏死性细胞死亡。然而，我们惊讶地发现，半胱天冬酶和RIPK3抑制剂不能完全抑制Tak1缺陷细胞的细胞死亡。从机制上讲，Tak1缺陷型巨噬细胞和成纤维细胞中第三细胞死亡途径的执行是由RIPK1依赖的活性氧（ROS）快速积累介导的。相反，RIPK1的激活足以诱导细胞死亡。因此，TAK1的缺失导致非典型的细胞死亡，这是由RIPK1诱导的氧化应激介导的半胱天冬酶和坏死性凋亡抑制，以进一步确保诱导细胞死亡。
Programmed cell death (PCD) occurs in several forms including apoptosis and necroptosis. Apoptosis is executed by the activation of caspases, while necroptosis is dependent on the receptor interacting protein kinase 3 (RIPK3). Precise control of cell death is crucial for tissue homeostasis. Indeed, necroptosis is triggered by caspase inhibition to ensure cell death. Here we identified a previously uncharacterized cell death pathway regulated by TAK1, which is unexpectedly provoked by inhibition of caspase activity and necroptosis cascades. Ablation of TAK1 triggers spontaneous death in macrophages. Simultaneous inhibition of caspases and RIPK3 did not completely restore cell viability. Previous studies demonstrated that loss of TAK1 in fibroblasts causes TNF-induced apoptosis and that additional inhibition of caspase leads to necroptotic cell death. However, we surprisingly found that caspase and RIPK3 inhibitions do not completely suppress cell death in Tak1-deficient cells. Mechanistically, the execution of the third cell death pathway in Tak1-deficient macrophages and fibroblasts were mediated by RIPK1-dependent rapid accumulation of reactive oxygen species (ROS). Conversely, activation of RIPK1 was sufficient to induce cell death. Therefore, loss of TAK1 elicits noncanonical cell death which is mediated by RIPK1-induced oxidative stress upon caspase and necroptosis inhibition to further ensure induction of cell death.