Heisler David B, Kudryashova Elena, Grinevich Dmitry O, Suarez Cristian, Winkelman Jonathan D, Birukov Konstantin G, Kotha Sainath R, Parinandi Narasimham L, Vavylonis Dimitrios, Kovar David R, Kudryashov Dmitri S
Department of Chemistry and Biochemistry, The Ohio State University, Columbus, OH 43210, USA. The Ohio State Biochemistry Program, The Ohio State University, Columbus, OH 43210, USA.
Department of Chemistry and Biochemistry, The Ohio State University, Columbus, OH 43210, USA.
Science. 2015 Jul 31;349(6247):535-9. doi: 10.1126/science.aab4090.
The actin cross-linking domain (ACD) is an actin-specific toxin produced by several pathogens, including life-threatening spp. of Vibrio cholerae, Vibrio vulnificus, and Aeromonas hydrophila. Actin cross-linking by ACD is thought to lead to slow cytoskeleton failure owing to a gradual sequestration of actin in the form of nonfunctional oligomers. Here, we found that ACD converted cytoplasmic actin into highly toxic oligomers that potently "poisoned" the ability of major actin assembly proteins, formins, to sustain actin polymerization. Thus, ACD can target the most abundant cellular protein by using actin oligomers as secondary toxins to efficiently subvert cellular functions of actin while functioning at very low doses.
肌动蛋白交联结构域(ACD)是由几种病原体产生的一种肌动蛋白特异性毒素,包括霍乱弧菌、创伤弧菌和嗜水气单胞菌等可危及生命的菌种。ACD介导的肌动蛋白交联被认为会导致细胞骨架缓慢衰竭,这是由于肌动蛋白以无功能寡聚体的形式逐渐被隔离。在此,我们发现ACD将细胞质肌动蛋白转化为剧毒寡聚体,这些寡聚体有效地“毒害”了主要的肌动蛋白组装蛋白——formin维持肌动蛋白聚合的能力。因此,ACD可以利用肌动蛋白寡聚体作为次级毒素靶向细胞内最丰富的蛋白质,从而在极低剂量下起作用时有效地破坏肌动蛋白的细胞功能。