A Conserved Structural Motif Mediates Retrograde Trafficking of Shiga Toxin Types 1 and 2.
A Conserved Structural Motif Mediates Retrograde Trafficking of Shiga Toxin Types 1 and 2.
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DOI：
10.1111/tra.12338
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发表时间：
2015-12
期刊：
影响因子：
--
通讯作者：
Mukhopadhyay S
中科院分区：
文献类型：
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作者：
Selyunin AS;Mukhopadhyay S
志贺毒素产生菌(STEC)产生两种志贺毒素(STX)：STX1和STX2。毒素A-亚基阻止蛋白质合成，而B-亚基介导逆行运输。STEC感染没有明确的治疗方法，人们对产生用于治疗的毒素转运抑制剂的兴趣越来越大。然而，全面了解毒素贩运的机制对于药物开发是至关重要的。虽然STX2在体内的毒性更大，但以前的研究主要集中在STX1B亚单位(STX1B)的贩运上。在这里，我们表明，与STX1B相比，STx2的B亚基(STx2B)向高尔基体运输的动力学较慢。尽管存在这种差异，但与STX1B类似，STX2B的内吞体到高尔基体的运输不涉及通过降解的晚期内吞体内进行运输，而是依赖于动力素II、epsinR、逆聚体和Synaxin5。重要的是，更多的实验表明，STx2B(β4-β5环)中的一个表面暴露的环是其内体向高尔基体运输所必需的。我们先前证明，STX1B相应的β4-β5环中的残基是与STX1B特异的内体受体GPP130相互作用以及内体到高尔基体运输所必需的。总体而言，STX1B和STX2B共享一条共同的途径，并使用类似的结构基序来运输高尔基体，这表明内体分选的潜在机制可能在进化上是保守的。
Shiga toxin-producing E. coli (STEC) produce two types of Shiga toxin (STx): STx1 and STx2. The toxin A-subunits block protein synthesis while the B-subunits mediate retrograde trafficking. STEC infections do not have definitive treatments, and there is growing interest in generating toxin transport inhibitors for therapy. However, a comprehensive understanding of the mechanisms of toxin trafficking is essential for drug development. While STx2 is more toxic in vivo, prior studies focused on STx1 B-subunit (STx1B) trafficking. Here, we show that, compared to STx1B, trafficking of the B-subunit of STx2 (STx2B) to the Golgi occurs with slower kinetics. Despite this difference, similar to STx1B, endosome-to-Golgi transport of STx2B does not involve transit through degradative late endosomes and is dependent on dynamin II, epsinR, retromer and syntaxin5. Importantly, additional experiments show that a surface-exposed loop in STx2B (β4-β5 loop) is required for its endosome-to-Golgi trafficking. We previously demonstrated that residues in the corresponding β4-β5 loop of STx1B are required for interaction with GPP130, the STx1B-specific endosomal receptor, and for endosome-to-Golgi transport. Overall, STx1B and STx2B share a common pathway and use a similar structural motif to traffic to the Golgi, suggesting that the underlying mechanisms of endosomal sorting may be evolutionarily conserved.