Nature Communications (Apr 2023)

A bacterial autotransporter impairs innate immune responses by targeting the transcription factor TFE3

  • Atri Ta,
  • Rafael Ricci-Azevedo,
  • Swathy O. Vasudevan,
  • Skylar S. Wright,
  • Puja Kumari,
  • Morena S. Havira,
  • Meera Surendran Nair,
  • Vijay A. Rathinam,
  • Sivapriya Kailasan Vanaja

DOI
https://doi.org/10.1038/s41467-023-37812-2
Journal volume & issue
Vol. 14, no. 1
pp. 1 – 17

Abstract

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Abstract 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.