Vibrio MARTX toxin effectors in signaling and pathogenesis

项目摘要 细菌 协调一致 自动处理 秘而不宣 秘而不宣 中央部分 经常协调分泌的毒力因子，以微调宿主在感染期间的反应。这些 事件可以包括毒素抵消或放大另一种毒素的影响。多功能- 重复序列毒素(MARTX)是一种大的分泌蛋白，是一种独特的 毒素和多效应器输送系统。与许多细菌蛋白毒素类似，MARTX毒素是 从细菌中分离出来，然后在宿主细胞质膜上形成一个孔。 T 在移位后 这种毒素是一种自动处理半胱氨酸蛋白酶结构域，通过结合肌醇来激活 六烷基磷酸。CPD介导的大分子多肽自身蛋白降解导致“MARTX”的释放 效应器“到细胞胞浆，在那里它们可以自由地在细胞内移动，接触细胞靶点，并 发挥它们的毒性作用。有100多种不同的细菌分类群携带MARTX毒素。在世界各地 不同物种，MARTX 他们 在一起 化学计量比 机制 在一起 汇辑 MARTX 能不能 这 致命性。 弧菌 毒素 这 讯号 毒素携带多达5个效应域，选自10个已知的效应域。 因此被称为“集束炸弹”。这些毒素的一个重要特征是所有的效应器都是L墨水 在单个多肽中同时、在相同的时间、以相同的速度输送到相同的细胞 比率虽然以前的研究采用了简化论的方法来确定 关于单个效应域的作用，人们对这些效应器如何传递知之甚少。 可能协同作用促进感染。此外，由于水平基因转移，毒素效应器 可以频繁变化，导致新的毒素类型。因此，相同的效应域在不同的 毒素在细胞信号和对毒力的贡献方面可能有上下文相关的差异。这 影响不同临床分离株的致病潜能，甚至在同一细菌种内也是如此。在……里面 更新研究，我们将重点研究不同组合的MARTX毒素效应器如何协同增强 这项研究将集中在肌动蛋白交联型MARTX效应器如何发现霍乱弧菌和 创伤杆菌可以对宿主细胞信号进行重新编程。我们将进一步询问效应器如何在相同的 然后补充或覆盖这个信号程序，以最佳方式促进毒力。然后我们将扩大规模 研究其他MARTX毒素，以探索其他组合是否也显示出上下文相关的影响 协调与病机。 T ， E a T f N L

Project Summary Bacteria coordinated autoprocessing secreted secreted central portion of often coordinate secreted virulence factors to fine-tune he host response during infection. These events can include toxins counteracting or amplifying effects of another toxin. Multifunctional- repeats-in toxin (MARTX) toxins are large, secreted proteins that are a unique hybrids of toxins and multi-effector delivery systems. Similar to many bacterial protein toxins, MARTX toxins are from the bacteria and then form a pore in the host cell plasma membrane. t After translocation of the the toxin, an autoprocessing cysteine protease domain is activated by binding inositol hexakisphosphate. CPD-mediated autoproteolysis of the large polypeptide results in release of the “MARTX effectors” to the cell cytosol, where they are free to move throughout the cell to access cellular targets and to exert their toxic effects. There are over 100 different bacterial taxa that carry a MARTX toxin. Across the different species, MARTX They together stoichiometric mechanism together repertoire MARTX could this virulence. Vibrio toxin this signal toxins carry up to 5 effector domains, selected from ten known effector domains. have thus been called “cluster bombs”. An important feature of these toxins is hat all the effectors l inked in a single polypeptide are delivered simultaneously to the same cell at the same time, at equal ratio. While previous studies have employed a reductionist approach to determine the of action of individual effector domains, little is known about how these ffector ctivities delivered may act in synergy to promote infection. Further, due to horizontal gene transfer, the toxin effector can change frequently resulting in novel toxinotypes. Thus, the same effector domain in a different toxins may have context-dependent differences in cell signaling and contribution to virulenc. This impac the pathogenic potential o different clinical isolates, even within the same bacterial species. In renewal study, we will focus on how different combinations of MARTX toxin effectors synergize to enhance The study will focus on how the actin crosslinking MARTX effector found i both Vibrio cholerae and vulnificus can reprogram host cell signaling. We wil further ask how effectors co-delivered on the same then complement or override this signaling program to optimally promote virulence. We will then expand study into other MARTX toxins to explore if other combinations also show context-dependent impact on coordination and pathogenesis. t , e a t f n l