Multifunctional autoprocessing repeats-in-toxin (MARTX) toxins are pore-forming bacterial toxins that translocate multiple functionally independent effector domains into a target eukaryotic cell. Vibrio cholerae colonizes intestinal epithelial cells (IECs) and uses a MARTX toxin with three effector domains-an actin cross-linking domain (ACD), a Rho inactivation domain (RID), and an α/β hydrolase domain (ABH)-to suppress innate immunity and enhance colonization. We investigated whether these multiple catalytic enzymes delivered from a single toxin functioned in a coordinated manner to suppress intestinal innate immunity. Using cultured human IECs, we demonstrated that ACD-induced cytoskeletal collapse activated extracellular signal-regulated kinase, p38, and c-Jun amino-terminal kinase mitogen-activated protein kinase (MAPK) signaling to elicit a robust proinflammatory response characterized by the secretion of interleukin-8 (IL-8; also called CXCL8) and the expression of CXCL8, tumor necrosis factor (TNF), and other proinflammatory genes. However, RID and ABH, which are naturally delivered together with ACD, blocked MAPK activation through Rac1 and thus prevented ACD-induced inflammation. RID also abolished IL-8 secretion induced by heat-killed bacteria, TNF, or latrunculin A. Thus, MARTX toxins use enzymatic multifunctionality to silence the host response to bacterial factors and to the damage caused by the toxins. Furthermore, these data show how V. cholerae MARTX toxin suppresses intestinal inflammation and contributes to cholera being classically defined as a noninflammatory diarrheal disease.

中文翻译：

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霍乱弧菌 MARTX 毒素在诱导肌动蛋白细胞骨架塌陷之前沉默对细胞骨架损伤的炎症反应。

多功能自动加工毒素内重复序列 (MARTX) 毒素是一种成孔细菌毒素，可将多个功能独立的效应结构域转移到目标真核细胞中。霍乱弧菌定植于肠上皮细胞 (IEC) 并使用具有三个效应域（肌动蛋白交联域 (ACD)、Rho 失活域 (RID) 和 α/β 水解酶域 (ABH)）的 MARTX 毒素来抑制先天免疫和增强定植。我们研究了从单一毒素传递的这些多种催化酶是否以协调的方式发挥作用以抑制肠道先天免疫。使用培养的人类 IEC，我们证明了 ACD 诱导的细胞骨架塌陷激活了细胞外信号调节激酶 p38，和 c-Jun 氨基末端激酶丝裂原活化蛋白激酶 (MAPK) 信号传导以引发强烈的促炎反应，其特征是分泌白细胞介素 8 (IL-8；也称为 CXCL8) 和 CXCL8、肿瘤坏死因子的表达。 TNF) 和其他促炎基因。然而，与 ACD 一起自然递送的 RID 和 ABH 通过 Rac1 阻断 MAPK 激活，从而防止 ACD 诱导的炎症。RID 还消除了由热灭活细菌、TNF 或 latrunculin A 诱导的 IL-8 分泌。因此，MARTX 毒素使用酶多功能来抑制宿主对细菌因子的反应和毒素造成的损害。此外，这些数据显示了 V.