CA-074Me Protection against Anthrax Lethal Toxin
CA-074Me Protection against Anthrax Lethal Toxin
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DOI：
10.1128/iai.00730-09
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发表时间：
2009-10-01
影响因子：
3.1
通讯作者：
Moayeri, Mahtab
中科院分区：
文献类型：
--
作者：
Newman, Zachary L.;Leppla, Stephen H.;Moayeri, Mahtab
炭疽致死毒素（LT）激活某些近交系小鼠巨噬细胞中的NLRP 1b（NALP 1b）炎性小体和半胱天冬酶-1，但其发生机制尚不清楚。我们在这里报告，类似于几个NLRP 3（NALP 3，cryopyrin）激活刺激，LT激活的NLRP 1 B炎性小体涉及溶酶体膜透化（LMP）和随后的细胞质组织蛋白酶B的活动。CA-074 Me是一种有效的组织蛋白酶B抑制剂，可保护LT敏感性巨噬细胞免于细胞死亡并阻止caspase-1的活化。然而，RNA干扰敲低组织蛋白酶B表达不能阻止LT介导的细胞死亡，表明CA-074 Me也可能作用于LMP期间释放的其他细胞蛋白酶。CA-074 Me似乎在LT易位至胞质溶胶（如通过促分裂原活化蛋白激酶激酶切割评估的）、K+流出和蛋白酶体活性的下游起作用。组织蛋白酶B的细胞质活性的初始增加发生在caspase-1激活的同时或之前不久，但在与细胞溶解密切相关的较大规模的溶酶体不稳定之前。我们目前的结果表明，LMP可能参与NLRP 1b炎性小体的激活。
Anthrax lethal toxin (LT) activates the NLRP1b (NALP1b) inflammasome and caspase-1 in macrophages from certain inbred mouse strains, but the mechanism by which this occurs is poorly understood. We report here that similar to several NLRP3 (NALP3, cryopyrin)-activating stimuli, LT activation of the NLRP1b inflammasome involves lysosomal membrane permeabilization (LMP) and subsequent cytoplasmic cathepsin B activity. CA-074Me, a potent cathepsin B inhibitor, protects LT-sensitive macrophages from cell death and prevents the activation of caspase-1. RNA interference knockdown of cathepsin B expression, however, cannot prevent LT-mediated cell death, suggesting that CA-074Me may also act on other cellular proteases released during LMP. CA-074Me appears to function downstream of LT translocation to the cytosol (as assessed by mitogen-activated protein kinase kinase cleavage), K+ effluxes, and proteasome activity. The initial increase in cytoplasmic activity of cathepsin B occurs at the same time or shortly before caspase-1 activation but precedes a larger-scale lysosomal destabilization correlated closely with cytolysis. We present results suggesting that LMP may be involved in the activation of the NLRP1b inflammasome.