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首页> 外文期刊>The FEBS journal >RIPK1 can function as an inhibitor rather than an initiator of RIPK3-dependent necroptosis
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RIPK1 can function as an inhibitor rather than an initiator of RIPK3-dependent necroptosis

机译：RIPK1可以作为RIPK3依赖性坏死病的抑制剂而不是引发剂

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摘要

Tumour necrosis factor and lipopolysaccharide can promote a regulated form of necrosis, called necroptosis, upon inhibition of caspase activity in cells expressing receptor-interacting serine/threonine kinase (RIPK) 3. Because inhibitors of RIPK1 kinase activity such as necrostatin-1 block necroptosis in many settings, RIPK1 is thought to be required for activation of RIPK3, leading to necroptosis. However, here we show that, although necrostatin potently inhibited tumour necrosis factor-induced, lipopolysaccharide-induced and polyIC-induced necroptosis, RIPK1 knockdown unexpectedly potentiated this process. In contrast, RIPK3 knockdown potently suppressed necroptosis under the same conditions. Significantly, necrostatin failed to block necroptosis in the absence of RIPK1, indicating that its ability to suppress necroptosis was indeed RIPK1-dependent. These data argue that RIPK1 is dispensable for necroptosis and can act as an inhibitor of this process. Our observations also suggest that necrostatin enhances the inhibitory effects of RIPK1 on necroptosis, as opposed to blocking its participation in this process.
机译：在表达受体相互作用的丝氨酸/苏氨酸激酶（RIPK）的细胞中抑制半胱天冬酶活性后，肿瘤坏死因子和脂多糖可促进一种坏死性坏死的调节形式，称为坏死性坏死。3.因为RIPK1激酶活性的抑制剂（如necrostatin-1）可阻断坏死性坏死。在许多设置中，RIPK1被认为是激活RIPK3所必需的，从而导致坏死。但是，在这里我们显示，尽管坏死抑制素有效抑制肿瘤坏死因子诱导的脂多糖诱导的和polyIC诱导的坏死性肾炎，但RIPK1的抑制却意外地增强了这一过程。相比之下，在相同条件下，RIPK3基因敲低可有效抑制坏死性坏死。值得注意的是，在没有RIPK1的情况下，坏死抑制素未能阻断坏死性硬化，表明其抑制坏死性硬化的能力确实是RIPK1依赖性的。这些数据表明，RIPK1对于坏死病是必不可少的，并且可以作为该过程的抑制剂。我们的观察结果还表明，坏死抑制素增强了RIPK1对坏死病的抑制作用，而不是阻止它参与该过程。

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