Manganese blocks intracellular trafficking of Shiga toxin and protects against Shiga toxicosis.
Manganese blocks intracellular trafficking of Shiga toxin and protects against Shiga toxicosis.
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DOI：
10.1126/science.1215930
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发表时间：
2012-01-20
期刊：
影响因子：
--
通讯作者：
Linstedt AD
中科院分区：
文献类型：
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作者：
Mukhopadhyay S;Linstedt AD
产生滋贺毒素（STx）的细菌感染每年导致100多万人死亡，并且没有明确的治疗方法。为了发挥其细胞毒性作用，STx通过逆行膜运输侵入细胞，逃避溶酶体降解途径。我们发现，广泛使用的金属锰（Mn 2+）阻止内体到高尔基体的运输STx，并导致其在溶酶体中的降解。Mn2+靶向循环高尔基体蛋白GPP130，STx在对照细胞中结合，分选成高尔基体定向的内体小管，绕过溶酶体。在组织培养细胞中，Mn2+处理产生了3800的保护因子，对STx诱导的细胞死亡。此外，注射无毒剂量的Mn 2+的小鼠对致死性STx攻击具有完全抗性。因此，Mn 2+可以代表用于治疗STx感染的低成本治疗剂。
Infections with Shiga toxin (STx)–producing bacteria cause more than a million deaths each year and have no definitive treatment. To exert its cytotoxic effect, STx invades cells through retrograde membrane trafficking, escaping the lysosomal degradative pathway. We found that the widely available metal manganese (Mn2+) blocked endosome-to-Golgi trafficking of STx and caused its degradation in lysosomes. Mn2+ targeted the cycling Golgi protein GPP130, which STx bound in control cells during sorting into Golgi-directed endosomal tubules that bypass lysosomes. In tissue culture cells, treatment with Mn2+ yielded a protection factor of 3800 against STx-induced cell death. Furthermore, mice injected with nontoxic doses of Mn2+ were completely resistant to a lethal STx challenge. Thus, Mn2+ may represent a low-cost therapeutic agent for the treatment of STx infections.