TY - JOUR
T1 - A bacterial autotransporter impairs innate immune responses by targeting the transcription factor TFE3
AU - Ta, Atri
AU - Ricci-Azevedo, Rafael
AU - Vasudevan, Swathy O.
AU - Wright, Skylar S.
AU - Kumari, Puja
AU - Havira, Morena S.
AU - Surendran Nair, Meera
AU - Rathinam, Vijay A.
AU - Vanaja, Sivapriya Kailasan
N1 - Funding Information:
This work was supported by the National Institutes of Health (NIH) (AI132850 to S.K.V. and AI119015 to V.R.). We thank Dr. John Leong for the EHEC O island mutant library, Dr. Kate Fitzgerald for HEK293T cells, and Dr. Rosa Puertollano and Dr. Jose Martina for Tfe3−/−and isogenic wild-type RAW264.7 macrophages. We gratefully acknowledge the quantitative proteomics analysis conducted by Dr. Jeremy L. Balsbaugh and Dr. Jennifer C. Liddle of the UConn Proteomics & Metabolomics Facility, a component of the Center for Open Research Resources and Equipment at the University of Connecticut.
Funding Information:
This work was supported by the National Institutes of Health (NIH) (AI132850 to S.K.V. and AI119015 to V.R.). We thank Dr. John Leong for the EHEC O island mutant library, Dr. Kate Fitzgerald for HEK293T cells, and Dr. Rosa Puertollano and Dr. Jose Martina for Tfe3 and isogenic wild-type RAW264.7 macrophages. We gratefully acknowledge the quantitative proteomics analysis conducted by Dr. Jeremy L. Balsbaugh and Dr. Jennifer C. Liddle of the UConn Proteomics & Metabolomics Facility, a component of the Center for Open Research Resources and Equipment at the University of Connecticut. −/−
Publisher Copyright:
© 2023, The Author(s).
PY - 2023/12
Y1 - 2023/12
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-023-37812-2
DO - 10.1038/s41467-023-37812-2
M3 - Article
C2 - 37041208
AN - SCOPUS:85152300448
SN - 2041-1723
VL - 14
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 2035
ER -