Unique features in the intracellular transport of typhoid toxin revealed by a genome-wide screen
Unique features in the intracellular transport of typhoid toxin revealed by a genome-wide screen
复制标题
DOI：
10.1371/journal.ppat.1007704
复制
发表时间：
2019-04-01
期刊：
影响因子：
6.7
通讯作者：
Galan, Jorge E.
中科院分区：
文献类型：
--
作者：
Chang, Shu-Jung;Jin, Sheng Chih;Galan, Jorge E.
伤寒毒素是伤寒沙门氏菌和副伤寒沙门氏菌的毒力因子，导致人类伤寒。该毒素具有独特的结构，其五聚体B亚基由Plt B组成，与两个酶A亚基，ADP核糖基转移酶PltA和脱氧核糖核酸酶Cdt B连接。伤寒毒素是唯一适应人类，识别表面糖蛋白唾液酸聚糖终止于乙酰神经氨酸，这是优先表达的人类细胞。目前尚不清楚伤寒毒素在受体结合后转运至其细胞靶点的途径。通过全基因组CRISPR/Cas9介导的筛选，我们表征了伤寒毒素在人类细胞内转运的机制。我们发现伤寒毒素劫持逆行运输和内质网相关降解机制的特定元件，以到达靶细胞内的亚细胞目的地。我们的研究揭示了独特的和共同的特点，在运输机制的细菌毒素，可以作为基础的发展，新的抗毒素治疗strategies.Author summary伤寒毒素是一个重要的毒力因子的人类病原体伤寒沙门氏菌，伤寒的原因。该毒素由一个五聚体B亚基与两个酶促A亚基连接组成，导致不寻常的A2 B5构型。B亚基通过与特异性表面受体相互作用靶向毒素的酶活性。一旦内化，毒素必须通过特定的运输机制运输到其最终的亚细胞目的地。在这里，我们使用了多学科的方法来定义伤寒毒素利用的细胞内转运机制的细节。通过全基因组筛选，我们发现伤寒毒素利用逆行转运细胞机制的组分到达内质网，从那里通过内质网相关降解途径转运到细胞胞质溶胶。通过比较伤寒毒素的运输途径与其他毒素所利用的运输机制，我们已经定义了独特的一个共同的组成部分，运输这些毒素到他们的细胞目的地。这些研究为开发新的抗毒素治疗策略提供了基础。
Typhoid toxin is a virulence factor for Salmonella Typhi and Paratyphi, the cause of typhoid fever in humans. This toxin has a unique architecture in that its pentameric B subunit, made of PltB, is linked to two enzymatic A subunits, the ADP ribosyl transferase PltA and the deoxyribonuclease CdtB. Typhoid toxin is uniquely adapted to humans, recognizing surface glycoprotein sialoglycans terminated in acetyl neuraminic acid, which are preferentially expressed by human cells. The transport pathway to its cellular targets followed by typhoid toxin after receptor binding is currently unknown. Through a genome-wide CRISPR/Cas9-mediated screen we have characterized the mechanisms by which typhoid toxin is transported within human cells. We found that typhoid toxin hijacks specific elements of the retrograde transport and endoplasmic reticulum-associated degradation machineries to reach its subcellular destination within target cells. Our study reveals unique and common features in the transport mechanisms of bacterial toxins that could serve as the bases for the development of novel anti-toxin therapeutic strategies.Author summary Typhoid toxin is an important virulence factor for the human pathogen Salmonella Typhi, the cause of typhoid fever. This toxin is composed of a pentameric B subunit linked to two enzymatic A subunits, resulting in an unusual A2B5 configuration. The B subunit targets the toxin's enzymatic activities by interacting with specific surface receptors. Once internalized, the toxin must be transported to its final subcellular destination by specific transport mechanisms. Here we have used a multidisciplinary approach to define the details of the intracellular transport mechanisms utilized by typhoid toxin. Through a genome-wide screen, we found that typhoid toxin utilizes components of the retrograde transport cellular machinery to arrive to the endoplasmic reticulum, from where it is transported to the cell cytosol by the endoplasmic reticulum-associated degradation pathway. By comparing typhoid toxin's transport pathway with the transport mechanisms utilized by other toxins we have defined unique a common components that transport these toxins to their cellular destinations. These studies may provide the based for the development of novel anti-toxin therapeutic strategies.