Heat shock inhibits caspase-1 activity while also preventing its inflammasome-mediated activation by anthrax lethal toxin
Heat shock inhibits caspase-1 activity while also preventing its inflammasome-mediated activation by anthrax lethal toxin
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DOI：
10.1111/j.1462-5822.2008.01220.x
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发表时间：
2008-12-01
影响因子：
3.4
通讯作者：
Moayeri, Mahtab
中科院分区：
文献类型：
--
作者：
Levin, Tera C.;Wickliffe, Katherine E.;Moayeri, Mahtab
炭疽致死毒素(LT)迅速杀死某些品系小鼠的巨噬细胞，其机制依赖于蛋白酶体分解未知蛋白(S)，形成Nalp1b(NLRP1b)炎症体，随后激活caspase-1。我们报告说，热休克LT敏感的巨噬细胞通过抑制caspase-1的激活而迅速保护它们免受细胞溶解的影响，而不会对LT的内吞作用或已知的胞浆底物(丝裂原激活的蛋白激酶)的裂解产生上游影响。对LT的热休克保护机制独立于从头蛋白合成、HSP90活性、p38激活或蛋白酶体抑制，并且位于蛋白酶体裂解丝裂原激活的蛋白激酶和降解未知底物的下游。热休克对LT介导的caspase-1激活的抑制不是Nalp1b(NLRP1b)炎症小体所特有的，因为热休克也抑制NALP3(NLRP3)炎症小体介导的巨噬细胞caspase-1的激活。我们发现，热休克诱导原caspase-1与一个大的细胞复合体结合，可以阻止其激活。此外，虽然热休克重组caspase-1不影响其体外活性，但热休克细胞裂解产物完全抑制重组活性caspase-1的活性。我们的结果表明，热休克抑制活性caspase-1可以独立于炎症体平台，通过存在于完整的、功能正常的热休克细胞中的可滴定因子来实现。
Anthrax lethal toxin (LT) rapidly kills macrophages from certain mouse strains in a mechanism dependent on the breakdown of unknown protein(s) by the proteasome, formation of the Nalp1b (NLRP1b) inflammasome and subsequent activation of caspase-1. We report that heat-shocking LT-sensitive macrophages rapidly protects them against cytolysis by inhibiting caspase-1 activation without upstream effects on LT endocytosis or cleavage of the toxin's known cytosolic substrates (mitogen-activated protein kinases). Heat shock protection against LT occurred through a mechanism independent of de novo protein synthesis, HSP90 activity, p38 activation or proteasome inhibition and was downstream of mitogen-activated protein kinase cleavage and degradation of an unknown substrate by the proteasome. The heat shock inhibition of LT-mediated caspase-1 activation was not specific to the Nalp1b (NLRP1b) inflammasome, as heat shock also inhibited Nalp3 (NLRP3) inflammasome-mediated caspase-1 activation in macrophages. We found that heat shock induced pro-caspase-1 association with a large cellular complex that could prevent its activation. Additionally, while heat-shocking recombinant caspase-1 did not affect its activity in vitro, lysates from heat-shocked cells completely inhibited recombinant active caspase-1 activity. Our results suggest that heat shock inhibition of active caspase-1 can occur independently of an inflammasome platform, through a titratable factor present within intact, functioning heat-shocked cells.