DPP8 / 9抑制剂是功能性NLRP1等位基因的通用激活剂。,Cell Death & Disease

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DPP8 / 9抑制剂是功能性NLRP1等位基因的通用激活剂。
Cell Death & Disease ( IF 8.1 ) Pub Date : 2019-08-05 , DOI: 10.1038/s41419-019-1817-5
Kuo Gai ₁ , Marian C Okondo ₁ , Sahana D Rao ₂ , Ashley J Chui ₂ , Daniel P Ball ₁ , Darren C Johnson ₂ , Daniel A Bachovchin _{1,

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Affiliation

细胞内的致病结构或活性刺激炎症小体的形成，这些炎症小体募集并激活caspase-1，并触发炎性形式的细胞死亡，称为焦磷酸化。众所周知，哺乳动物的炎症小体传感器蛋白都可以检测一种特定类型的信号，例如双链DNA或细菌鞭毛蛋白。值得注意的是，NLRP1是第一个被发现形成炎症小体的蛋白质，但尚未确定NLRP1检测到的致病信号。NLRP1是高度多态的，即使在近交啮齿动物品系中也是如此，并且已经表明这些多样化的NLRP1等位基因可能已经进化为检测完全不同的刺激。有趣的是，最近显示丝氨酸蛋白酶DPP8和DPP9（DPP8 / 9）的抑制剂可激活人NLRP1，其同系物CARD8和几个小鼠NLRP1等位基因。这里，我们现在显示DPP8 / 9抑制剂激活了所有功能性啮齿动物NLRP1等位基因，表明DPP8 / 9抑制作用诱导了所有NLRP1蛋白检测到的信号。此外，我们发现NLRP1等位基因对DPP8 / 9抑制剂诱导的弓形虫和弓形虫诱导的凋亡的敏感性非常相似，这表明DPP8 / 9抑制表型是弓形虫的关键活性。总的来说，这项工作表明，高度多态的NLRP1炎性小体确实像其他哺乳动物的炎性小体一样感觉到特定的信号。提示DPP8 / 9抑制表型是弓形虫的关键活性。总体而言，这项工作表明，高度多态的NLRP1炎性小体确实像其他哺乳动物的炎性小体一样能感知特定的信号。提示DPP8 / 9抑制表型是弓形虫的关键活性。总体而言，这项工作表明，高度多态的NLRP1炎性小体确实像其他哺乳动物的炎性小体一样能感知特定的信号。

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DPP8/9 inhibitors are universal activators of functional NLRP1 alleles.

Intracellular pathogenic structures or activities stimulate the formation of inflammasomes, which recruit and activate caspase-1 and trigger an inflammatory form of cell death called pyroptosis. The well-characterized mammalian inflammasome sensor proteins all detect one specific type of signal, for example double-stranded DNA or bacterial flagellin. Remarkably, NLRP1 was the first protein discovered to form an inflammasome, but the pathogenic signal that NLRP1 detects has not yet been identified. NLRP1 is highly polymorphic, even among inbred rodent strains, and it has been suggested that these diverse NLRP1 alleles may have evolved to detect entirely different stimuli. Intriguingly, inhibitors of the serine proteases DPP8 and DPP9 (DPP8/9) were recently shown to activate human NLRP1, its homolog CARD8, and several mouse NLRP1 alleles. Here, we show now that DPP8/9 inhibitors activate all functional rodent NLRP1 alleles, indicating that DPP8/9 inhibition induces a signal detected by all NLRP1 proteins. Moreover, we discovered that the NLRP1 allele sensitivities to DPP8/9 inhibitor-induced and Toxoplasma gondii-induced pyroptosis are strikingly similar, suggesting that DPP8/9 inhibition phenocopies a key activity of T. gondii. Overall, this work indicates that the highly polymorphic NLRP1 inflammasome indeed senses a specific signal like the other mammalian inflammasomes.

更新日期：2019-08-05

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