Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
McGill University Research Centre on Complex Traits, McGill University, Montreal, Quebec, Canada.
Nat Microbiol. 2019 Sep;4(9):1516-1531. doi: 10.1038/s41564-019-0484-8. Epub 2019 Jul 8.
Salmonella presents a global public health concern. Central to Salmonella pathogenicity is an ability to subvert host defences through strategically targeting host proteins implicated in restricting infection. Therefore, to gain insight into the host-pathogen interactions governing Salmonella infection, we performed an in vivo genome-wide mutagenesis screen to uncover key host defence proteins. This revealed an uncharacterized role of CYRI (FAM49B) in conferring host resistance to Salmonella infection. We show that CYRI binds to the small GTPase RAC1 through a conserved domain present in CYFIP proteins, which are known RAC1 effectors that stimulate actin polymerization. However, unlike CYFIP proteins, CYRI negatively regulates RAC1 signalling, thereby attenuating processes such as macropinocytosis, phagocytosis and cell migration. This enables CYRI to counteract Salmonella at various stages of infection, including bacterial entry into non-phagocytic and phagocytic cells as well as phagocyte-mediated bacterial dissemination. Intriguingly, to dampen its effects, the bacterial effector SopE, a RAC1 activator, selectively targets CYRI following infection. Together, this outlines an intricate host-pathogen signalling interplay that is crucial for determining bacterial fate. Notably, our study also outlines a role for CYRI in restricting infection mediated by Mycobacterium tuberculosis and Listeria monocytogenes. This provides evidence implicating CYRI cellular functions in host defence beyond Salmonella infection.
沙门氏菌是全球公共卫生关注的一个问题。沙门氏菌的致病性的核心是通过有策略地靶向宿主蛋白来颠覆宿主防御，这些宿主蛋白涉及限制感染。因此，为了深入了解控制沙门氏菌感染的宿主-病原体相互作用，我们进行了体内全基因组诱变筛选，以发现关键的宿主防御蛋白。这揭示了 CYRI（FAM49B）在赋予宿主对沙门氏菌感染的抗性方面的一个未被描述的作用。我们表明，CYRI 通过 CYFIP 蛋白中存在的保守结构域与小分子 GTPase RAC1 结合，CYFIP 蛋白是已知的 RAC1 效应物，可刺激肌动蛋白聚合。然而，与 CYFIP 蛋白不同，CYRI 负调控 RAC1 信号通路，从而减弱了巨胞饮作用、吞噬作用和细胞迁移等过程。这使 CYRI 能够在感染的各个阶段对抗沙门氏菌，包括细菌进入非吞噬细胞和吞噬细胞以及吞噬细胞介导的细菌传播。有趣的是，为了抑制其作用，细菌效应蛋白 SopE（一种 RAC1 激活剂）在感染后专门针对 CYRI。总之，这概述了一个复杂的宿主-病原体信号相互作用，对于确定细菌的命运至关重要。值得注意的是，我们的研究还概述了 CYRI 在限制结核分枝杆菌和李斯特菌单核细胞增生症感染方面的作用。这为 CYRI 在宿主防御中的细胞功能超越沙门氏菌感染提供了证据。
