Vibrio MARTX toxin effectors in signaling and pathogenesis

项目摘要 细菌 协调 自动处理 分泌 分泌 中心部分 通常协调分泌的毒力因子以在感染期间微调宿主应答。这些 事件可以包括抵消或放大另一种毒素的作用的毒素。多功能- 重复序列毒素（MARTX）毒素是一种大的分泌蛋白，是一种独特的杂交体， 毒素和多效应传递系统。与许多细菌蛋白毒素类似，MARTX毒素是 然后在宿主细胞质膜上形成一个小孔。 不 易位后， 该毒素是一种自加工半胱氨酸蛋白酶结构域， 六磷酸盐CPD介导的大多肽的自蛋白水解导致“MARTX”的释放。 这些“效应子”可以自由地移动到细胞胞质溶胶中，在胞质溶胶中它们可以自由地移动到整个细胞中以接近细胞靶点， 发挥其毒性作用。有超过100种不同的细菌分类群携带MARTX毒素。各地 不同物种，MARTX 他们 一起 化学计量 机制 一起 汇辑 MARTX 可以 这 毒性。 弧菌 毒素 这 信号 毒素携带多达5个选自10个已知效应子结构域的效应子结构域。 因此被称为“集束炸弹”。这些毒素的一个重要特征是， 在同一时间，以相等的速率， 比例虽然以前的研究采用了还原主义的方法来确定 关于单个效应域的作用，很少有人知道这些效应域是如何传递的。 可以协同作用以促进感染。此外，由于水平基因转移，毒素效应子 可以频繁变化，从而产生新的毒素型。因此，在不同的基因组中，相同的效应子结构域可以是相同的。 毒素可能在细胞信号传导和对细胞毒性的贡献方面具有环境依赖性差异。这 影响不同临床分离株的致病潜力，甚至在相同的细菌物种内。在 更新研究，我们将重点关注MARTX毒素效应子的不同组合如何协同作用， 这项研究将集中在肌动蛋白交联MARTX效应如何在霍乱弧菌和 创伤可以重编程宿主细胞信号。我们将进一步询问效应器如何在相同的细胞上共同递送， 然后补充或覆盖这个信号程序，以最佳地促进毒力。我们将扩大 对其他MARTX毒素的研究，以探索其他组合是否也显示出对 协调和发病机制。 不 , 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