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首页> 外文期刊>The Journal of biological chemistry >Leukotoxin (Leukothera?) Targets Active Leukocyte Function Antigen-1 (LFA-1) Protein and Triggers a Lysosomal Mediated Cell Death Pathway
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Leukotoxin (Leukothera?) Targets Active Leukocyte Function Antigen-1 (LFA-1) Protein and Triggers a Lysosomal Mediated Cell Death Pathway

机译：白酮毒素（白蛋白酶？）靶向活性白细胞功能抗原-1（LFA-1）蛋白，并触发溶酶体介导的细胞死亡途径

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Leukotoxin (LtxA) is a protein toxin that is secreted from the oral bacterium, Aggregatibacter actinomycetemcomitans. LtxA targets specifically the β2 integrin, leukocyte function antigen-1 (LFA-1) on white blood cells (WBCs) and causes cell death. LtxA preferentially targets activated WBCs and is being developed as a therapeutic agent for the treatment of WBC diseases such as hematologic malignancies and autoimmune/inflammatory diseases. However, the mechanism by which interaction between LtxA and LFA-1 results in cell death is not well understood. Furthermore, how LtxA preferentially recognizes activated WBCs is not known. We show here that LtxA interacts specifically with LFA-1 in the active (exposed) conformation. In THP-1 monocytes, LtxA caused rapid activation of caspases, but LtxA could overcome the inhibition of caspases and still intoxicate. In contrast, inhibiting the vesicular trafficking pathway or cathepsin D release from the lysosome resulted in significant inhibition of LtxA-mediated cytotoxicity, indicating a more potent, lysosomal mediated cell death pathway. LtxA caused rapid disruption of the lysosomal membrane and release of lysosomal contents into the cytosol. Binding of LtxA to LFA-1 resulted in the internalization of both LtxA and LFA-1, with LtxA localizing specifically to the lysosomal compartment. To our knowledge, LtxA represents the first bacterial toxin shown to localize to the lysosome where it induces rapid cell death.
机译：白酮毒素（LTXA）是一种蛋白质毒素，其从口腔细菌分泌，聚合杆菌诱导症。 LTXA特别是β2整合蛋白，白细胞上白细胞（WBC）上的白细胞功能抗原-1（LFA-1）并导致细胞死亡。 LTXA优先靶向活化的WBC，并且正在作为治疗WBC疾病如血液学恶性肿瘤和自身免疫/炎性疾病的治疗剂。然而，LTXA和LFA-1之间相互作用的机制并不能很好地理解细胞死亡。此外，LTXA如何识别激活的WBC是未知的。我们在这里展示LTXA在主动（暴露）构象中具有LFA-1的互动。在THP-1单核细胞中，LTXA引起了胱天蛋白酶的快速活化，但LTXA可以克服血糖抑制，仍然醉化。相反，抑制来自溶酶体的囊泡贩运途径或组织蛋白酶D释放导致LTXA介导的细胞毒性的显着抑制，表明更有效，溶酶体介导的细胞死亡途径。 LTXA引起溶酶体膜的快速破坏溶酶体膜并释放到胞嘧啶中。 LTXA至LFA-1的结合导致LTXA和LFA-1的内化，LTXA本地化为溶酶体隔室。据我们所知，LTXA代表了第一个显示到溶酶体的细菌毒素，在那里诱导快速细胞死亡。

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