Activation of a c-Jun-NH2-terminal kinase pathway by the lethal toxin from Clostridium sordellii, TcsL-82, occurs independently of the toxin intrinsic enzymatic activity and facilitates small GTPase glucosylation
Activation of a c-Jun-NH2-terminal kinase pathway by the lethal toxin from Clostridium sordellii, TcsL-82, occurs independently of the toxin intrinsic enzymatic activity and facilitates small GTPase glucosylation
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DOI：
10.1111/j.1462-5822.2009.01314.x
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发表时间：
2009-07-01
影响因子：
3.4
通讯作者：
Popoff, Michel R.
中科院分区：
文献类型：
--
作者：
Geny, Blandine;Popoff, Michel R.
在本研究中，我们发现梭状芽胞杆菌（Clostridium sordellii, TcsL-82）的致死毒素激活了三条MAP激酶途径，但只有一种可渗透的特异性c- jun - nh2末端激酶（JNK）抑制剂，JNK抑制剂II，可以阻止毒素依赖性肌动蛋白解聚和细胞围成。我们发现，JNK的激活依赖于毒素n端结构域进入细胞质，因为巴菲霉素A1阻止了内吞囊泡的酸化和随后毒素n端结构域的细胞质易位，从而阻止了JNK的激活。JNK活性的抑制延迟了n端催化活性产生的小GTPase糖基化。使用缺乏udp -葡萄糖的细胞系突变体，我们观察到JNK的激活即使在没有小GTPase糖基化的情况下也会发生，因此，与毒素固有的催化活性无关。JNK激活对靶糖基化的促进作用似乎仅限于tcll -82，而不是大型梭状菌毒素的一般特征。事实上，虽然艰难梭菌毒素B也能激活JNK，但它并没有被观察到。
In the present study, we show that lethal toxin from Clostridium sordellii (TcsL-82) activates the three MAP kinase pathways, but that only a permeable and specific c-Jun-NH2-terminal kinase (JNK) inhibitor, JNK inhibitor II, prevents toxin-dependent actin depolymerization and cell rounding. We show that JNK activation is dependent on entry of the toxin N-terminal domain into the cytosol as bafilomycin A1, which prevents acidification of endocytic vesicle and subsequent cytosolic translocation of the toxin N-terminal domain, prevents JNK activation. Inhibition of JNK activity delays small GTPase glucosylation generated by N-terminal domain catalytic activity. Using a cell line mutant deficient in UDP-glucose, we observed that activation of JNK occurs even in the absence of small GTPase glucosylation and, thus, is independent of the toxin intrinsic catalytic activity. Facilitation of target glucosylation by JNK activation appeared to be restricted to TcsL-82 and was not a general feature of large clostridial toxins. Indeed, it was not observed with Toxin B from Clostridium difficile although this toxin also activates JNK.