While apoptosis has been considered to be identical to programmed cell death, necroptosis, which is morphologically related to necrosis, has emerged as a novel type of programmed cell death. Necroptosis depends on two structurally related kinases, receptor-interacting serine-threonine kinase (RIPK)1 and RIPK3. RIPK1 is activated through oligomerization of upstream adaptor molecules such as Fas-associated protein with death domain (FADD) and TNF receptor-associated death domain (TRADD) that are triggered by TNFα or Fas ligand. Activated RIPK1 subsequently interacts with and activates RIPK3, resulting in necroptosis. However, contribution of oxidative stress to execution of necroptosis is still controversial. We found that a selective inhibitor for RIPK1, necrostatin-1 (Nec-1) significantly blocked TNFα-induced cell death and ROS accumulation in NF-κB activation-deficient cells. This suggests that these cells mostly died by necroptosis upon TNFα stimulation. Intriguingly, an antioxidant, butylated hydroxyanisole (BHA) blocked TNFα-induced necroptosis and ROS accumulation in NF-κB activation-deficient cells. However, Nec-1, but not BHA, inhibited TNFα-induced phosphorylation of RIPK1 in these cells, suggesting that ROS play a crucial role in execution of necroptosis downstream of RIPK1 activation. Structural and functional analyses using BHA related compounds revealed that both tert-butyl and hydroxy groups of BHA are crucial for its anti-necroptotic function. Together, these results suggest that TNFα-induced necroptosis is tightly associated with oxidative stress, and oxidative stress is induced downstream of RIPK1 activation.

译文

虽然细胞凋亡被认为与程序性细胞死亡相同,但在形态上与坏死有关的坏死性坏死已成为一种新型的程序性细胞死亡。坏死性依赖于两种结构相关的激酶,受体相互作用的丝氨酸-苏氨酸激酶 (RIPK)1和ripk3。RIPK1通过由TNF α 或Fas配体触发的上游衔接子分子 (例如具有死亡结构域 (FADD) 和TNF受体相关死亡结构域 (TRADD) 的Fas相关蛋白) 的寡聚而被激活。激活的RIPK1随后与RIPK3相互作用并激活,导致坏死性。然而,氧化应激对坏死性坏死的影响仍然存在争议。我们发现RIPK1,necrostatin-1 (Nec-1) 的选择性抑制剂可显着阻止tnf α 诱导的NF-κ b活化缺陷细胞中的细胞死亡和ROS积累。这表明这些细胞在tnf α 刺激下大多死于坏死性。有趣的是,抗氧化剂丁基羟基茴香醚 (BHA) 阻止了tnf α 诱导的坏死和ROS在NF-κ b活化缺陷细胞中的积累。然而,Nec-1 (而不是BHA) 抑制了tnf α 诱导的这些细胞中RIPK1的磷酸化,这表明ROS在RIPK1激活下游的坏死性坏死中起着至关重要的作用。使用BHA相关化合物进行的结构和功能分析表明,BHA的叔丁基和羟基对于其抗坏死功能至关重要。总之,这些结果表明,tnf α 诱导的坏死性坏死与氧化应激密切相关,而氧化应激是在RIPK1激活的下游诱导的。

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