Newman Zachary L, Leppla Stephen H, Moayeri Mahtab
Bacterial Toxins and Therapeutics Section, Laboratory of Bacterial Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
Infect Immun. 2009 Oct;77(10):4327-36. doi: 10.1128/IAI.00730-09. Epub 2009 Jul 27.
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.
炭疽致死毒素（LT）可激活某些近交系小鼠巨噬细胞中的NLRP1b（NALP1b）炎性小体和半胱天冬酶-1，但对此过程发生的机制了解甚少。我们在此报告，与几种NLRP3（NALP3，冷吡啉）激活刺激相似，LT激活NLRP1b炎性小体涉及溶酶体膜通透性增加（LMP）及随后的细胞质组织蛋白酶B活性。强效组织蛋白酶B抑制剂CA-074Me可保护对LT敏感的巨噬细胞免于细胞死亡，并阻止半胱天冬酶-1的激活。然而，RNA干扰敲低组织蛋白酶B的表达并不能阻止LT介导的细胞死亡，这表明CA-074Me也可能作用于LMP过程中释放的其他细胞蛋白酶。CA-074Me似乎在LT转位至胞质溶胶（通过丝裂原活化蛋白激酶激酶裂解评估）、钾离子外流和蛋白酶体活性的下游发挥作用。组织蛋白酶B细胞质活性的最初增加与半胱天冬酶-1激活同时发生或稍早于其激活，但先于与细胞溶解密切相关的更大规模的溶酶体不稳定。我们给出的结果表明LMP可能参与NLRP1b炎性小体的激活。
