Hsp70 facilitates trans-membrane transport of bacterial ADP-ribosylating toxins into the cytosol of mammalian cells.
Hsp70 facilitates trans-membrane transport of bacterial ADP-ribosylating toxins into the cytosol of mammalian cells.
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DOI：
10.1038/s41598-017-02882-y
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发表时间：
2017-06-02
影响因子：
4.6
通讯作者：
Barth H
中科院分区：
文献类型：
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作者：
Ernst K;Schmid J;Beck M;Hägele M;Hohwieler M;Hauff P;Ückert AK;Anastasia A;Fauler M;Jank T;Aktories K;Popoff MR;Schiene-Fischer C;Kleger A;Müller M;Frick M;Barth H
二元肠毒素梭菌（C.）肉毒杆菌C2毒素、C.产气荚膜杆菌iota毒素和C.艰难梭菌毒素CDT由转运蛋白（B）和单独的非连接酶（A）组分组成。它们的B组分介导内吞摄取到哺乳动物细胞中，随后将A组分从酸性内体转运到胞质溶胶中，其中后者ADP-核糖基化G-肌动蛋白导致细胞变圆和细胞死亡，引起临床症状。蛋白质折叠酶，包括热休克蛋白90和肽基脯氨酰顺/反异构酶促进运输的A组分通过内体膜。在这里，我们确定了热休克蛋白70作为一种新的宿主细胞因子，特异性地与C2，iota和CDT毒素的A组分相互作用，以促进其运输到细胞胞质溶胶中。药理学Hsp 70抑制特异性地防止A组分进入细胞溶质的pH依赖性跨膜转运，从而保护活细胞和干细胞衍生的人小肠免于中毒。因此，Hsp 70抑制可能导致开发新的治疗策略来治疗与细菌ADP-核糖基化毒素相关的疾病。
Binary enterotoxins Clostridium (C.) botulinum C2 toxin, C. perfringens iota toxin and C. difficile toxin CDT are composed of a transport (B) and a separate non-linked enzyme (A) component. Their B-components mediate endocytic uptake into mammalian cells and subsequently transport of the A-components from acidic endosomes into the cytosol, where the latter ADP-ribosylate G-actin resulting in cell rounding and cell death causing clinical symptoms. Protein folding enzymes, including Hsp90 and peptidyl-prolyl cis/trans isomerases facilitate transport of the A-components across endosomal membranes. Here, we identified Hsp70 as a novel host cell factor specifically interacting with A-components of C2, iota and CDT toxins to facilitate their transport into the cell cytosol. Pharmacological Hsp70-inhibition specifically prevented pH-dependent trans-membrane transport of A-components into the cytosol thereby protecting living cells and stem cell-derived human miniguts from intoxication. Thus, Hsp70-inhibition might lead to development of novel therapeutic strategies to treat diseases associated with bacterial ADP-ribosylating toxins.