Chlamydia trachomatis induces the transcriptional activity of host YAP in a Hippo-independent fashion

Frontiers in Cellular and Infection Microbiology

Cellular and Infection Microbiology

Amanda J. Brinkworth¹  Rey A. Carabeo¹  Liam T. Caven² 

[1]Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, United States

[2]Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, United States

[3]School of Molecular Biosciences, College of Veterinary Medicine, Washington State University, Pullman, WA, United States

关键词: Chlamydia trachomatis;    host response;    YAP;    pathogen-directed host transcription;    Hippo kinase;   

DOI  :  10.3389/fcimb.2023.1098420

 received in 2022-11-14, accepted in 2023-02-08,  发布年份 2023

来源: Frontiers

【 摘 要 】

IntroductionThe obligate intracellular pathogen Chlamydia trachomatis is the causative agent of the most common bacterial sexually transmitted disease worldwide. While the host response to infection by this pathogen has been well characterized, it remains unclear to what extent host gene expression during infection is the product of Chlamydia-directed modulation of host transcription factors.MethodsTo identify transcription factors potentially modulated by Chlamydia during infection, we infected immortalized endocervical epithelial cells (End1/E6E7) with the anogenital C. trachomatis serovar L2, harvesting polyadenylated RNA for bulk RNA-sequencing. Subsequent experiments elucidating the mechanism of infection-mediated YAP activation assayed YAP target gene expression via qRT-PCR, YAP nuclear translocation via quantitative immunofluorescence, and YAP phosphorylation via Western blotting.ResultsRNA sequencing of Chlamydia-infected endocervical epithelial cells revealed gene expression consistent with activity of YAP, a transcriptional coactivator implicated in cell proliferation, wound healing, and fibrosis. After confirming induction of YAP target genes during infection, we observed an infection-dependent increase in YAP nuclear translocation sensitive to inhibition of bacterial protein synthesis. While Hippo-mediated phosphoinhibition of YAP at S127 was unaffected by C. trachomatis infection, Hippo-independent phosphorylation at Y357 was increased. Infection did not enhance nuclear translocation of Y357F mutant YAP, illustrating a requirement for phosphorylation at this residue. Pharmacological inhibition of host Src-family kinase activity attenuated YAP Y357 phosphorylation, but not nuclear translocation – which was instead sensitive to inhibition of Abl.DiscussionOur results define a transcriptome-altering mechanism of pathogen-directed YAP activation that bypasses canonical inhibition by the Hippo kinase cascade, with a potential link to chlamydial fibrosis and other advanced disease sequelae. Additional study is required to determine the specific role of infection-associated Y357 phosphorylation and Abl activity in chlamydial induction of YAP.

【 授权许可】

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Copyright © 2023 Caven, Brinkworth and Carabeo