Anthrax lethal factor cleavage of Nlrp1 is required for activation of the inflammasome.
Anthrax lethal factor cleavage of Nlrp1 is required for activation of the inflammasome.
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DOI：
10.1371/journal.ppat.1002638
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发表时间：
2012
期刊：
影响因子：
6.7
通讯作者：
Moayeri M
中科院分区：
文献类型：
--
作者：
Levinsohn JL;Newman ZL;Hellmich KA;Fattah R;Getz MA;Liu S;Sastalla I;Leppla SH;Moayeri M
nod样受体（NLR）蛋白（Nlrps）是细胞质传感器，负责通过未知机制检测病原体和危险相关的分子模式。它们响应广泛的细胞内危险信号而激活，导致炎性小体的形成、caspase-1激活、快速程序性细胞死亡（焦亡）和IL-1β和IL-18的成熟。炭疽致死毒素（LT）通过激活nod样受体（NLR） Nlrp1炎性体，诱导小鼠和大鼠巨噬细胞的caspase-1依赖性焦亡。在这里，我们发现LT切割大鼠Nlrp1，这种切割是毒素诱导的炎性体激活、IL-1 β释放和巨噬细胞焦亡所必需的。这些结果发现了一种以前未被认识的NLR激活机制和一种新的、生理上相关的LT蛋白底物。炭疽致死毒素（LT）是一种蛋白酶，可以诱导巨噬细胞快速死亡，并伴有促炎细胞因子的激活和释放。先前确定的这种毒素的细胞底物尚未显示在这种快速细胞死亡中起作用。本报告确定了一种新的LT底物，并证明巨噬细胞死亡需要毒素对其进行切割。底物Nlrp1是细胞内危险传感器大家族的一员。这些传感器一旦被激活，就会形成一种叫做炎性体的多蛋白复合物，对宿主的先天免疫反应至关重要。这些传感器的激活机制尚不清楚。本研究证明了Nlrp1的裂解介导激活，这是首次报道炎症小体激活的直接生化机制。
NOD-like receptor (NLR) proteins (Nlrps) are cytosolic sensors responsible for detection of pathogen and danger-associated molecular patterns through unknown mechanisms. Their activation in response to a wide range of intracellular danger signals leads to formation of the inflammasome, caspase-1 activation, rapid programmed cell death (pyroptosis) and maturation of IL-1β and IL-18. Anthrax lethal toxin (LT) induces the caspase-1-dependent pyroptosis of mouse and rat macrophages isolated from certain inbred rodent strains through activation of the NOD-like receptor (NLR) Nlrp1 inflammasome. Here we show that LT cleaves rat Nlrp1 and this cleavage is required for toxin-induced inflammasome activation, IL-1 β release, and macrophage pyroptosis. These results identify both a previously unrecognized mechanism of activation of an NLR and a new, physiologically relevant protein substrate of LT. Anthrax lethal toxin (LT) is a protease which can induce rapid death of macrophages accompanied by activation and release of pro-inflammatory cytokines. The previously identified cellular substrates for this toxin have not been shown to play a role in this rapid cell death. This report identifies a new substrate for LT, and demonstrates that its cleavage by the toxin is required for macrophage death. The substrate, Nlrp1, is a member of a large family of intracellular sensors of danger. These sensors, once activated, form a multiprotein complex called the inflammasome and are essential to the host innate immune response. The mechanism of activation for these sensors is not known. The demonstration of cleavage-mediated activation of Nlrp1 in this study represents the first report on a direct biochemical mechanism for inflammasome activation.
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影响因子：
1.6
作者：
Park, S;Leppla, SH
通讯作者：
Leppla, SH
影响因子：
3.1
作者：
Liao, Kuo-Chieh;Mogridge, Jeremy
通讯作者：
Mogridge, Jeremy
影响因子：
3.4
作者：
Levin, Tera C.;Wickliffe, Katherine E.;Moayeri, Mahtab
通讯作者：
Moayeri, Mahtab
DOI：
10.1073/pnas.79.10.3162
发表时间：
1982-01-01
期刊：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA-BIOLOGICAL SCIENCES
影响因子：
--
作者：
LEPPLA, SH
通讯作者：
LEPPLA, SH
影响因子：
3.1
作者：
Newman, Zachary L.;Leppla, Stephen H.;Moayeri, Mahtab
通讯作者：
Moayeri, Mahtab