Cathepsin B-mediated Autophagy Flux Facilitates the Anthrax Toxin Receptor 2-mediated Delivery of Anthrax Lethal Factor into the Cytoplasm
Cathepsin B-mediated Autophagy Flux Facilitates the Anthrax Toxin Receptor 2-mediated Delivery of Anthrax Lethal Factor into the Cytoplasm
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DOI：
10.1074/jbc.m109.065813
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发表时间：
2010-01-15
影响因子：
4.8
通讯作者：
Kim, Sung Ouk
中科院分区：
文献类型：
--
作者：
Ha, Soon-Duck;Ham, Boram;Kim, Sung Ouk
炭疽致死毒素（LeTx）是由炭疽杆菌分泌的一种毒力因子，一旦释放到细胞质中，对大多数细胞具有直接的细胞毒性作用。LeTx的蛋白水解活性组分（致死因子（LF））的细胞质递送通过转运蛋白组分（保护性抗原）进行，所述转运蛋白组分与称为炭疽毒素受体（ANTXR）1和2的两种已知表面受体中的任一种相互作用。我们发现ANTXR 2介导的LF的胞质递送是由组织蛋白酶B（CTSB）介导的，并且需要溶酶体与含LeTx的内体融合。此外，保护性抗原与ANXTR 1或2的结合触发了自噬，这促进了ANTXR 2相关LF的细胞质递送。我们发现，虽然用膜渗透性CTSB抑制剂CA 074-Me或CTSB缺陷细胞处理的细胞在含有LC 3的自噬空泡与溶酶体的融合方面没有缺陷，但自噬通量显着延迟。这些结果表明CTSB依赖的自噬通量增强了ANTXR 2介导的LF胞质递送。
Anthrax lethal toxin (LeTx) is a virulence factor secreted by Bacillus anthracis and has direct cytotoxic effects on most cells once released into the cytoplasm. The cytoplasmic delivery of the proteolytically active component of LeTx, lethal factor (LF), is carried out by the transporter component, protective antigen, which interacts with either of two known surface receptors known as anthrax toxin receptor (ANTXR) 1 and 2. We found that the cytoplasmic delivery of LF by ANTXR2 was mediated by cathepsin B (CTSB) and required lysosomal fusion with LeTx-containing endosomes. Also, binding of protective antigen to ANXTR1 or 2 triggered autophagy, which facilitated the cytoplasmic delivery of ANTXR2-associated LF. We found that whereas cells treated with the membrane-permeable CTSB inhibitor CA074-Me- or CTSB-deficient cells had no defect in fusion of LC3-containing autophagic vacuoles with lysosomes, autophagic flux was significantly delayed. These results suggested that the ANTXR2-mediated cytoplasmic delivery of LF was enhanced by CTSB-dependent autophagic flux.