Key Laboratory of Zoonosis, Ministry of Education, Institute of Zoonosis, Jilin University, Changchun, China.
Tumor Hospital of Jilin Province, Changchun, China; and.
J Immunol. 2022 Aug 1;209(3):488-497. doi: 10.4049/jimmunol.2200001. Epub 2022 Jul 15.
Mammalian GTPase-activating proteins (GAPs) can inhibit innate immunity signaling in a spatiotemporal fashion; however, the role of bacterial GAPs in mediating innate immunity remains unknown. In this study, we show that BspI, a type IV secretion system (T4SS) effector protein, containing a GAP domain at the C terminus, negatively regulates proinflammatory responses and host protection to infection in a mouse model. In macrophages, BspI inhibits the activation of inositol-requiring enzyme 1 (IRE1) kinase, but it does not inhibit activation of ATF6 and PERK. BspI suppresses induction of proinflammatory cytokines via inhibiting the activity of IRE1 kinase caused by VceC, a type IV secretion system effector protein that localizes to the endoplasmic reticulum. Ectopically expressed BspI interacts with IRE1 in HeLa cells. The inhibitory function of BspI depends on its GAP domain but not on interaction with small GTPase Ras-associated binding protein 1B (RAB1B). Collectively, these data support a model where BspI, in a GAP domain-dependent manner, inhibits activation of IRE1 to prevent proinflammatory cytokine responses.
哺乳动物鸟嘌呤核苷酸交换因子（GAPs）可以时空方式抑制先天免疫信号；然而，细菌 GAP 在介导先天免疫中的作用尚不清楚。在这项研究中，我们表明，BspI，一种含有 C 末端 GAP 结构域的 IV 型分泌系统（T4SS）效应蛋白，在小鼠模型中负调控先天免疫反应和宿主对 感染的保护作用。在巨噬细胞中，BspI 抑制肌醇需求酶 1（IRE1）激酶的激活，但不抑制 ATF6 和 PERK 的激活。BspI 通过抑制定位于内质网的 IV 型分泌系统效应蛋白 VceC 引起的 IRE1 激酶活性来抑制促炎细胞因子的诱导。异位表达的 BspI 在 HeLa 细胞中与 IRE1 相互作用。BspI 的抑制功能取决于其 GAP 结构域，但不依赖于与小 GTP 酶 Ras 相关结合蛋白 1B（RAB1B）的相互作用。总之，这些数据支持这样一种模型，即 BspI 以 GAP 结构域依赖性方式抑制 IRE1 的激活，以防止促炎细胞因子反应。
