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Regulation of endo-lysosomal pathway and autophagic flux by broad-spectrum antipathogen inhibitor ABMA.
The FEBS Journal ( IF 5.5 ) Pub Date : 2020-01-04 , DOI: 10.1111/febs.15201 Yu Wu 1 , Claire Boulogne 2 , Stefan Carle 3 , Maria Podinovskaia 4 , Holger Barth 3 , Anne Spang 4 , Jean-Christophe Cintrat 5 , Daniel Gillet 1 , Julien Barbier 1
The FEBS Journal ( IF 5.5 ) Pub Date : 2020-01-04 , DOI: 10.1111/febs.15201 Yu Wu 1 , Claire Boulogne 2 , Stefan Carle 3 , Maria Podinovskaia 4 , Holger Barth 3 , Anne Spang 4 , Jean-Christophe Cintrat 5 , Daniel Gillet 1 , Julien Barbier 1
Affiliation
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The endo‐lysosome system is involved in endocytosis, protein sorting, and degradation as well as autophagy. Numerous toxins and pathogens exploit this system to enter host cells and exert their deleterious effects. Modulation of host endo‐lysosome pathway may restrict multiple toxins intoxication as well as pathogen infection. ABMA, selected from a high‐throughput screening against the cytotoxicity of ricin toxin, exhibits a broad‐spectrum antitoxin and antipathogen activity. Here, we show that ABMA selectively retains endocytosed protein and toxin to late endosomes and thus delaying their intracellular trafficking. It also impairs the autophagic flux by excessive fusion of late endosomes and autophagosomes. Its exclusive action on late endosomes and corresponding consequences on the endo‐lysosomal pathway and autophagic flux are distinct from known inhibitors such as bafilomycin A1, EGA, or chloroquine. Hence, besides being a broad‐spectrum inhibitor of endocytosed toxins and pathogens, ABMA may serve as a molecular tool to dissect endo‐lysosome system‐related cellular physiology and mechanisms of pathogenesis.
中文翻译：
广谱抗病原体抑制剂ABMA调节溶酶体途径和自噬通量。
溶酶体系统参与胞吞作用，蛋白质分选，降解以及自噬。许多毒素和病原体利用该系统进入宿主细胞并发挥其有害作用。宿主溶酶体途径的调节可能会限制多种毒素中毒以及病原体感染。ABMA是从针对蓖麻毒素毒素的细胞毒性的高通量筛选中选择的，具有广谱抗毒素和抗病原体活性。在这里，我们显示ABMA选择性地将胞吞蛋白和毒素保留到晚期内体，从而延迟了它们的细胞内运输。它也通过晚期内体和自噬体的过度融合而损害自噬通量。它对晚期内体的排他性作用以及对内体溶酶体途径和自噬通量的相应后果与已知的抑制剂（例如巴氟霉素A1，EGA或氯喹）不同。因此，ABMA除了是一种广谱抑制内吞毒素和病原体的抑制剂外，还可以作为一种分子工具来分析与内溶酶体系统有关的细胞生理学和发病机理。
更新日期：2020-01-04
中文翻译：
广谱抗病原体抑制剂ABMA调节溶酶体途径和自噬通量。
溶酶体系统参与胞吞作用，蛋白质分选，降解以及自噬。许多毒素和病原体利用该系统进入宿主细胞并发挥其有害作用。宿主溶酶体途径的调节可能会限制多种毒素中毒以及病原体感染。ABMA是从针对蓖麻毒素毒素的细胞毒性的高通量筛选中选择的，具有广谱抗毒素和抗病原体活性。在这里，我们显示ABMA选择性地将胞吞蛋白和毒素保留到晚期内体，从而延迟了它们的细胞内运输。它也通过晚期内体和自噬体的过度融合而损害自噬通量。它对晚期内体的排他性作用以及对内体溶酶体途径和自噬通量的相应后果与已知的抑制剂（例如巴氟霉素A1，EGA或氯喹）不同。因此，ABMA除了是一种广谱抑制内吞毒素和病原体的抑制剂外，还可以作为一种分子工具来分析与内溶酶体系统有关的细胞生理学和发病机理。
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