Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
Tri-Institutional PhD Program in Chemical Biology, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
Cell Death Dis. 2019 Aug 5;10(8):587. doi: 10.1038/s41419-019-1817-5.
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.
细胞内病原体结构或活动刺激炎性小体的形成，炎性小体募集并激活半胱天冬酶-1 并引发一种称为细胞焦亡的炎症形式的细胞死亡。已充分表征的哺乳动物炎性小体传感器蛋白均检测到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性小体的蛋白质，但 NLRP1 检测到的致病信号尚未确定。NLRP1 高度多态性，甚至在近交系啮齿动物中也是如此，有人提出，这些不同的 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，丝氨酸蛋白酶 DPP8 和 DPP9（DPP8/9）抑制剂最近被证明可激活人 NLRP1、其同源物 CARD8 和几种小鼠 NLRP1 等位基因。在这里，我们现在表明 DPP8/9 抑制剂激活所有功能性啮齿动物 NLRP1 等位基因，表明 DPP8/9 抑制诱导所有 NLRP1 蛋白检测到的信号。此外，我们发现 DPP8/9 抑制剂诱导的和弓形虫诱导的细胞焦亡对 NLRP1 等位基因的敏感性非常相似，表明 DPP8/9 抑制模拟了弓形虫的关键活性。总体而言，这项工作表明高度多态性的 NLRP1 炎性小体确实像其他哺乳动物炎性小体一样检测到特定信号。
