Distinct regions of NLRP1B are required to respond to anthrax lethal toxin and metabolic inhibition.
Distinct regions of NLRP1B are required to respond to anthrax lethal toxin and metabolic inhibition.
复制标题
NLRP1B 的不同区域需要对炭疽致死毒素和代谢抑制作出反应。
DOI：
10.1128/iai.02167-14
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发表时间：
2014
影响因子：
3.1
通讯作者：
Mogridge,Jeremy
中科院分区：
文献类型：
--
作者：
Neiman-Zenevich,Jana;Liao,Kuo-Chieh;Mogridge,Jeremy
模式识别受体监测感染或细胞功能障碍的迹象，并通过启动免疫反应来应对这些事件。 NLRP1B 是一种受体，激活后会募集多个 procaspase-1 拷贝，促进细胞因子加工和称为细胞焦亡的促炎性细胞死亡形式。当炭疽致命毒素从蛋白质上裂解氨基末端片段时，NLRP1B 就会检测到该毒素。此外，当细胞缺乏葡萄糖或用代谢抑制剂处理时，NLRP1B 会被激活，但 NLRP1B 感知胞质 ATP 减少的机制尚不清楚。在这里，我们讨论了 NLRP1B 的这两个激活信号是否汇聚在一个共同的传感系统上。我们发现，缺乏氨基末端区域的 NLRP1B 突变体表现出一些自发活性，并且无法被致命毒素进一步激活。然而，该突变体在 ATP 耗尽的细胞中仍然被激活，表明氨基末端区域不是 NLRP1B 的唯一传感结构域。 NLRP1B 富含亮氨酸的重复结构域的诱变提供了证据，表明该结构域参与受体的自身抑制，但所测试的突变体没有一个在感知激活信号方面存在明显缺陷。比较 NLRP1B 的两个等位基因对代谢抑制剂的反应不同，但对致命毒素的反应不同，结果发现，由外显子重复引起的寻找功能域 (FIIND) 中的重复序列有助于检测 ATP 耗尽。这些结果表明 NLRP1B 的不同区域检测到激活信号。
Pattern recognition receptors monitor for signs of infection or cellular dysfunction and respond to these events by initiating an immune response. NLRP1B is a receptor that upon activation recruits multiple copies of procaspase-1, which promotes cytokine processing and a proinflammatory form of cell death termed pyroptosis. NLRP1B detects anthrax lethal toxin when the toxin cleaves an amino-terminal fragment from the protein. In addition, NLRP1B is activated when cells are deprived of glucose or treated with metabolic inhibitors, but the mechanism by which the resulting reduction in cytosolic ATP is sensed by NLRP1B is unknown. Here, we addressed whether these two activating signals of NLRP1B converge on a common sensing system. We show that an NLRP1B mutant lacking the amino-terminal region exhibits some spontaneous activity and fails to be further activated by lethal toxin. This mutant was still activated in cells depleted of ATP, however, indicating that the amino-terminal region is not the sole sensing domain of NLRP1B. Mutagenesis of the leucine-rich repeat domain of NLRP1B provided evidence that this domain is involved in autoinhibition of the receptor, but none of the mutants tested was specifically defective at sensing activating signals. Comparison of two alleles of NLRP1B that differed in their response to metabolic inhibitors, but not to lethal toxin, led to the finding that a repeated sequence in the function to find domain (FIIND) that arose from exon duplication facilitated detection of ATP depletion. These results suggest that distinct regions of NLRP1B detect activating signals.