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Tamoxifen blocks retrograde trafficking of Shiga toxin 1 and 2 and protects against lethal toxicosis.
Life Science Alliance ( IF 4.4 ) Pub Date : 2019-06-26 , DOI: 10.26508/lsa.201900439
Andrey S Selyunin 1 , Steven Hutchens 1 , Stanton F McHardy 2 , Somshuvra Mukhopadhyay 3
Affiliation  

Shiga toxin 1 (STx1) and 2 (STx2), produced by Shiga toxin-producing Escherichia coli, cause lethal untreatable disease. The toxins invade cells via retrograde trafficking. Direct early endosome-to-Golgi transport allows the toxins to evade degradative late endosomes. Blocking toxin trafficking, particularly at the early endosome-to-Golgi step, is appealing, but transport mechanisms of the more disease-relevant STx2 are unclear. Using data from a genome-wide siRNA screen, we discovered that disruption of the fusion of late endosomes, but not autophagosomes, with lysosomes blocked the early endosome-to-Golgi transport of STx2. A subsequent screen of clinically approved lysosome-targeting drugs identified tamoxifen (TAM) to be a potent inhibitor of the trafficking and toxicity of STx1 and STx2 in cells. The protective effect was independent of estrogen receptors but dependent on the weak base property of TAM, which allowed TAM to increase endolysosomal pH and alter endosomal dynamics. Importantly, TAM treatment enhanced survival of mice injected with a lethal dose of STx1 or STx2. Thus, it may be possible to repurpose TAM for treating Shiga toxin-producing E. coli infections.

中文翻译:

他莫昔芬阻止志贺毒素1和2的逆行贩运,并防止致命的中毒。

产生志贺毒素的大肠杆菌产生的志贺毒素1(STx1)和2(STx2),引起致命的不可治愈的疾病。毒素通过逆行运输侵入细胞。早期的内体到高尔基体的直接转运使毒素逃避了降解的晚期内体。阻断毒素的运输,特别是在从内体到高尔基体的早期阶段,是有吸引力的,但是与疾病相关性更强的STx2的运输机制尚不清楚。使用来自全基因组siRNA筛选的数据,我们发现晚期内体而不是自噬体与溶酶体的融合破坏,阻断了STx2从内体到高尔基体的早期转运。随后的临床批准的靶向溶酶体的药物筛选确定他莫昔芬(TAM)是STx1和STx2在细胞中的运输和毒性的有效抑制剂。保护作用与雌激素受体无关,但取决于TAM的弱碱基特性,这使得TAM可以增加溶酶体的pH值并改变内体动力学。重要的是,TAM治疗可提高注射了致死剂量的STx1或STx2的小鼠的存活率。因此,有可能将TAM重新用于治疗产生志贺毒素的产品大肠杆菌感染。
更新日期:2020-08-21
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