An anthrax lethal factor mutant that is defective at causing pyroptosis retains proapoptotic activity.
An anthrax lethal factor mutant that is defective at causing pyroptosis retains proapoptotic activity.
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DOI：
10.1111/j.1742-4658.2009.07458.x
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发表时间：
2010-01
期刊：
影响因子：
--
通讯作者：
Mogridge J
中科院分区：
文献类型：
--
作者：
Ngai S;Batty S;Liao KC;Mogridge J
炭疽致命毒素会引起某些细胞类型的死亡，如巨噬细胞，并在其他细胞中引起各种细胞功能障碍。总的来说，这些影响抑制了先天和适应性免疫系统，使炭疽芽孢杆菌在哺乳动物宿主中存活和增殖。毒素引起的各种影响部分归因于它对靶细胞信号通路的干扰。致死因子（LF）是毒素的蛋白水解成分，它通过毒素的细胞结合成分保护性抗原传递到细胞质后，切割丝裂原活化蛋白激酶（MAPKK）家族的6个成员。切割这些MAPKKs的作用是干扰ERK、p38和JNK信号。在这里，我们描述了LF突变体LF- k518e /E682G，它在引起RAW 264.7细胞的焦亡和在异源表达系统中激活Nlrp1b炎性体方面存在缺陷。LF-K518E/E682G不表现出整体功能损伤，然而，因为它能够下调ERK途径，但不下调p38或JNK途径。此外，LF-K518E/E682G有效地杀死黑色素瘤细胞，这些细胞在致命毒素或ERK通路的药理抑制作用下发生凋亡。我们的研究结果表明，LF-K518E/E682G在切割参与Nlrp1b炎性体激活的底物时存在缺陷。
Anthrax lethal toxin triggers death in some cell types, such as macrophages, and causes a variety of cellular dysfunctions in others. Collectively, these effects dampen the innate and adaptive immune systems to allow Bacillus anthracis to survive and proliferate in the mammalian host. The diverse effects caused by the toxin have in part been attributed to its interference with signaling pathways in target cells. Lethal factor (LF) is the proteolytic component of the toxin, which cleaves six members of the mitogen activated protein kinase kinase (MAPKK) family after being delivered to the cytosol by the cell-binding component of the toxin, protective antigen. The effect of cleaving these MAPKKs is to interfere with ERK, p38 and JNK signaling. Here we characterize an LF mutant, LF-K518E/E682G, that is defective at causing pyroptosis in RAW 264.7 cells and at activating the Nlrp1b inflammasome in a heterologous expression system. LF-K518E/E682G does not exhibit an overall impairment of function, however, because it is able to downregulate the ERK pathway, but not the p38 or JNK pathways. Furthermore, LF-K518E/E682G efficiently killed melanoma cells, which were shown previously to undergo apoptosis in response to lethal toxin or to pharmacological inhibition of the ERK pathway. Our results suggest that LF-K518E/E682G is defective at cleaving a substrate involved in the activation of the Nlrp1b inflammasome.
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DOI：
10.1152/ajpregu.00593.2003
发表时间：
2004-04-01
影响因子：
2.8
作者：
Cui, XZ;Moayeri, M;Eichacker, PQ
通讯作者：
Eichacker, PQ
影响因子：
2.9
作者：
Miller, CJ;Elliott, JL;Collier, RJ
通讯作者：
Collier, RJ
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：
Wickliffe, Katherine E.;Leppla, Stephen H.;Moayeri, Mahtab
通讯作者：
Moayeri, Mahtab
影响因子：
5.7
作者：
Abi-Habib, RJ;Urieto, JO;Frankel, AE
通讯作者：
Frankel, AE