Eeyarestatin 1 interferes with both retrograde and anterograde intracellular trafficking pathways.
Eeyarestatin 1 interferes with both retrograde and anterograde intracellular trafficking pathways.
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DOI：
10.1371/journal.pone.0022713
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Spooner RA
中科院分区：
文献类型：
--
作者：
Aletrari MO;McKibbin C;Williams H;Pawar V;Pietroni P;Lord JM;Flitsch SL;Whitehead R;Swanton E;High S;Spooner RA
小分子Eeyarestatin I(ESI)抑制内质网(ER)-胞浆错位和ERAD(ER相关蛋白降解)底物的降解。蓖麻毒素和志贺/志贺样毒素(SLTx)等毒素被内吞并贩运到急诊室。它们的催化亚单位被认为利用类似ERAD的机制从内质网错位到胞浆中，在胞浆中有一部分从ERAD过程中解离，恢复催化构象，并破坏他们的细胞靶标。因此，我们研究了ESI作为一种潜在的毒素错位抑制剂。使用细胞毒性测量，我们没有发现ESI作为内质网毒素错位的抑制剂，而是发现对于SLTx，ESI处理细胞是通过减少毒素向ER的输送而起到保护作用的。对标记的SLTx及其B链(没有有毒的A链)运输的显微镜观察显示，其在核周围位置的积累延迟，通过检查代谢性标记的SLTx B链在跨高尔基体池中被确认为高尔基体。该药物还降低了白喉毒素的内体转运速度，白喉毒素从酸化的内吞体内进入胞浆，并推迟了高尔基体特异的多糖修饰和tsO45 VSV-G蛋白的最终质膜出现，tsO45 VSV-G蛋白是顺行转运的经典标志。ESI作用于一个或多个在囊泡运输过程中起作用的成分，同时至少有一个逆行运输途径，即蓖麻毒素，保持不受干扰。
The small molecule Eeyarestatin I (ESI) inhibits the endoplasmic reticulum (ER)-cytosol dislocation and subsequent degradation of ERAD (ER associated protein degradation) substrates. Toxins such as ricin and Shiga/Shiga-like toxins (SLTx) are endocytosed and trafficked to the ER. Their catalytic subunits are thought to utilise ERAD-like mechanisms to dislocate from the ER into the cytosol, where a proportion uncouples from the ERAD process, recovers a catalytic conformation and destroys their cellular targets. We therefore investigated ESI as a potential inhibitor of toxin dislocation. Using cytotoxicity measurements, we found no role for ESI as an inhibitor of toxin dislocation from the ER, but instead found that for SLTx, ESI treatment of cells was protective by reducing the rate of toxin delivery to the ER. Microscopy of the trafficking of labelled SLTx and its B chain (lacking the toxic A chain) showed a delay in its accumulation at a peri-nuclear location, confirmed to be the Golgi by examination of SLTx B chain metabolically labelled in the trans-Golgi cisternae. The drug also reduced the rate of endosomal trafficking of diphtheria toxin, which enters the cytosol from acidified endosomes, and delayed the Golgi-specific glycan modifications and eventual plasma membrane appearance of tsO45 VSV-G protein, a classical marker for anterograde trafficking. ESI acts on one or more components that function during vesicular transport, whilst at least one retrograde trafficking pathway, that of ricin, remains unperturbed.
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影响因子：
7.8
作者：
Fu, LW;Sztul, E
通讯作者：
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DOI：
10.1016/j.bbrc.2007.08.057
发表时间：
2007-10-26
影响因子：
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作者：
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影响因子：
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作者：
通讯作者：
--
影响因子：
7.8
作者：
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通讯作者：
Helenius, A