PDF(Pubmed)
Abstract：
Nigericin, an ionophore derived from Streptomyces hygroscopicus, is arguably the most commonly used tool compound to study the NLRP3 inflammasome. Recent findings, however, showed that nigericin also activates the NLRP1 inflammasome in human keratinocytes. In this study, we resolve the mechanistic basis of nigericin-driven NLRP1 inflammasome activation. In multiple nonhematopoietic cell types, nigericin rapidly and specifically inhibits the elongation stage of the ribosome cycle by depleting cytosolic potassium ions. This activates the ribotoxic stress response (RSR) sensor kinase ZAKα, p38, and JNK, as well as the hyperphosphorylation of the NLRP1 linker domain. As a result, nigericin-induced pyroptosis in human keratinocytes is blocked by extracellular potassium supplementation, ZAKα knockout, or pharmacologic inhibitors of ZAKα and p38 kinase activities. By surveying a panel of ionophores, we show that electroneutrality of ion movement is essential to activate ZAKα-driven RSR and a greater extent of K+ depletion is necessary to activate ZAKα-NLRP1 than NLRP3. These findings resolve the mechanism by which nigericin activates NLRP1 in nonhematopoietic cell types and demonstrate an unexpected connection between RSR, perturbations of potassium ion flux, and innate immunity.
摘要：
Nigericin,一种来源于吸湿性链霉菌的离子载体，可以说是研究NLRP3炎性体最常用的工具化合物。最近的发现,然而,表明，尼日利亚霉素也激活人角质形成细胞中的NLRP1炎性体。在这项研究中,我们解决了尼日利亚素驱动的NLRP1炎症小体激活的机制基础。在多种非造血细胞类型中，nigericin通过消耗细胞溶质钾离子来快速且特异性地抑制核糖体循环的延伸阶段。这激活了利波毒性应激反应（RSR）传感器激酶ZAKα，p38和JNK,以及NLRP1接头结构域的过度磷酸化。因此,人角质形成细胞中的尼格霉素诱导的焦亡被细胞外钾补充阻断，ZAKα基因敲除,或ZAKα和p38激酶活性的药物抑制剂。通过测量一组离子载体，我们表明，离子运动的电中性对于激活ZAKα驱动的RSR至关重要，并且与NLRP3相比，激活ZAKα-NLRP1需要更大程度的K消耗。这些发现解决了Nigericin在非造血细胞类型中激活NLRP1的机制，并证明了RSR之间的意外联系，钾离子通量的扰动，和先天免疫。
