A nontoxigenic form of Shiga toxin 2 suppresses the production of amyloid b by altering the intracellular transport of amyloid precursor protein through its receptor-binding B-subunit
A nontoxigenic form of Shiga toxin 2 suppresses the production of amyloid b by altering the intracellular transport of amyloid precursor protein through its receptor-binding B-subunit
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志贺毒素 2 的非产毒形式通过其受体结合 B 亚基改变淀粉样前体蛋白的细胞内转运，从而抑制淀粉样蛋白 b 的产生
DOI：
10.1016/j.bbrc.2021.04.015
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发表时间：
2021
影响因子：
3.1
通讯作者：
Kiyotaka Nishikawa
中科院分区：
文献类型：
--
作者：
Waka Sato;Miho Watanabe-Takahashi;Takashi Hamabata;Koichi Furukawa;Satoru Funamoto;Kiyotaka Nishikawa
淀粉样β肽（Aβ）在神经元细胞和大脑细胞外区域的积累是阿尔茨海默病（AD）的主要原因；因此，抑制 Aβ 积累为 AD 治疗策略提供了一种有前景的方法。 Aβ 是由淀粉样前体蛋白 (APP) 在内吞位于质膜中的 APP 后，在晚期/再循环内体中连续蛋白水解而产生的。然后 Aβ 以游离形式或外泌体结合形式从细胞中释放。志贺毒素（Stx）是肠出血性大肠杆菌的主要毒力因子。最近，我们发现Stx亚型之一Stx2a通过其受体结合B亚基内吞后具有独特的细胞内转运途径。 Stx2a 的一部分可以被转运到晚期/再循环内体，然后在溶酶体酸性室中降解，尽管通常 Stx 以逆行方式转运到高尔基体，然后再转运到内质网。在这项研究中，我们发现用突变体 Stx2a (mStx2a) 处理表达 APP 的细胞，由于催化 A 亚基的突变而缺乏细胞毒活性，刺激 APP 转运至酸性区室，从而导致 APP 降解和 Aβ 量减少。 mStx2a 治疗还抑制 Aβ 的细胞外释放。因此，mStx2a可能提供一种通过调节APP的细胞内转运来抑制Aβ产生的新策略。
Accumulation of amyloid-β peptide (Aβ) in neuronal cells and in the extracellular regions in the brain is a major cause of Alzheimer’s disease (AD); therefore, inhibition of Aβ accumulation offers a promising approach for therapeutic strategies against AD. Aβ is produced by sequential proteolysis of amyloid precursor protein (APP) in late/recycling endosomes after endocytosis of APP located in the plasma membrane. Aβ is then released from cells in a free form or in an exosome-bound form. Shiga toxin (Stx) is a major virulence factor of enterohemorrhagicEscherichia coli. Recently, we found that one of the Stx subtypes, Stx2a, has a unique intracellular transport route after endocytosis through its receptor-binding B-subunit. A part of Stx2a can be transported to late/recycling endosomes and then degraded in a lysosomal acidic compartment, although in general Stx is transported to the Golgi and then to the endoplasmic reticulum in a retrograde manner. In this study, we found that treatment of APP-expressing cells with a mutant Stx2a (mStx2a), lacking cytotoxic activity because of mutations in the catalytic A-subunit, stimulated the transport of APP to the acidic compartment, which led to degradation of APP and a reduction in the amount of Aβ. mStx2a-treatment also inhibited the extracellular release of Aβ. Therefore, mStx2a may provide a new strategy to inhibit the production of Aβ by modulating the intracellular transport of APP.