Department of Immunology, UConn Health School of Medicine, 263 Farmington Ave, Farmington, CT, 06030, USA.
Arvinas, Inc., 5 Science Park, New Haven, CT, 06511, USA.
Nat Commun. 2023 Apr 11;14(1):2035. doi: 10.1038/s41467-023-37812-2.
Type I interferons (IFNs) are consequential cytokines in antibacterial defense. Whether and how bacterial pathogens inhibit innate immune receptor-driven type I IFN expression remains mostly unknown. By screening a library of enterohemorrhagic Escherichia coli (EHEC) mutants, we uncovered EhaF, an uncharacterized protein, as an inhibitor of innate immune responses including IFNs. Further analyses identified EhaF as a secreted autotransporter-a type of bacterial secretion system with no known innate immune-modulatory function-that translocates into host cell cytosol and inhibit IFN response to EHEC. Mechanistically, EhaF interacts with and inhibits the MiT/TFE family transcription factor TFE3 resulting in impaired TANK phosphorylation and consequently, reduced IRF3 activation and type I IFN expression. Notably, EhaF-mediated innate immune suppression promotes EHEC colonization and pathogenesis in vivo. Overall, this study has uncovered a previously unknown autotransporter-based bacterial strategy that targets a specific transcription factor to subvert innate host defense.
I 型干扰素（IFNs）是抗菌防御中的重要细胞因子。细菌病原体是否以及如何抑制先天免疫受体驱动的 I 型 IFN 表达在很大程度上尚不清楚。通过筛选肠出血性大肠杆菌（EHEC）突变体文库，我们发现一种未被表征的蛋白 EhaF 是先天免疫反应（包括 IFNs）的抑制剂。进一步的分析确定 EhaF 是一种分泌型自转运蛋白——一种具有未知先天免疫调节功能的细菌分泌系统——可转运到宿主细胞质中并抑制 EHEC 对 IFN 的反应。在机制上，EhaF 与 MiT/TFE 家族转录因子 TFE3 相互作用并抑制其活性，导致 TANK 磷酸化减少，进而 IRF3 激活和 I 型 IFN 表达减少。值得注意的是，EhaF 介导的先天免疫抑制促进了 EHEC 在体内的定植和发病机制。总的来说，这项研究揭示了一种以前未知的基于自转运蛋白的细菌策略，该策略针对特定的转录因子来颠覆先天宿主防御。
