The Chlamydia trachomatis Tarp effector targets the Hippo pathway

Shehat, Michael G.; Aranjuez, George F.; Kim, Jongeon; Jewett, Travis J.

doi:10.1016/j.bbrc.2021.05.057

Cited by 7 publications

(7 citation statements)

References 29 publications

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“…Our results put forward a potential mechanism for the recent report of YAP activation at an earlier stage of chlamydial infection (Shehat et al, 2021). The authors present the significant infection-and TarP-dependent induction of YAP target genes TEAD4 and XIAP at 8 hpi, contending the observed loss of YAP and target expression in a TarP-deficient infection indicates TarP may inhibit YAP degradation.…”

Section: Discussionsupporting

confidence: 62%

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

Caven

Brinkworth

Carabeo

2022

Preprint

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Chronic infection of the female reproductive tract by Chlamydia trachomatis can cause fibrotic infertility. Thought to be the product of the immune response to infection, the incidence of fibrosis observed in subclinical or asymptomatic infections remains unexplained. Recent work demonstrates infection induces the pro-fibrotic process of epithelial-to-mesenchymal transition (EMT), but the mechanisms underlying this are unclear. We show the Chlamydia-induced host transcriptome includes targets of YAP, a pro-EMT transcriptional coactivator. We observe increased YAP nuclear translocation and pro-EMT YAP target gene induction during infection, bypassing YAP inhibition by the Hippo kinase cascade, and acting via YAP tyrosine phosphoactivation associated with host Src activity, and the myosin-modulating chlamydial effector CTL0480. Comparing the host transcriptome of a ΔCTL0480-mutant infection to wild-type infection revealed consistent reduction in known YAP target expression, as well as attenuated induction of EMT. Our results define a mechanism for Chlamydia-directed modulation of host gene expression, providing insight into chlamydial induction of immune-independent fibrosis.

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Section: Discussionsupporting

confidence: 62%

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

Caven

Brinkworth

Carabeo

2022

Preprint

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“…Phosphorylated TarP interacts with a multitude of host cell signalling molecules, as well as phosphatidylinositol 3-kinase (PI3K) and SHC-transforming protein 1 (SHC1), involved in diverse cell functions (e.g. growth, differentiation, motility, survival) ( Shehat et al., 2021 ). TarP was also discovered to impair the highly conserved Hippo signalling pathway in infected epithelial cells, a previously unknown chlamydia-affected pathway involved in cell proliferation and death ( Shehat et al., 2021 ).…”

Section: Type III Secretion System and Effector Proteinsmentioning

confidence: 99%

Molecular pathogenesis of Chlamydia trachomatis

Jury,

Fleming,

Huston

et al. 2023

Front. Cell. Infect. Microbiol.

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Chlamydia trachomatis is a strict intracellular human pathogen. It is the main bacterial cause of sexually transmitted infections and the etiologic agent of trachoma, which is the leading cause of preventable blindness. Despite over 100 years since C. trachomatis was first identified, there is still no vaccine. However in recent years, the advancement of genetic manipulation approaches for C. trachomatis has increased our understanding of the molecular pathogenesis of C. trachomatis and progress towards a vaccine. In this mini-review, we aimed to outline the factors related to the developmental cycle phase and specific pathogenesis activity of C. trachomatis in order to focus priorities for future genetic approaches. We highlight the factors known to be critical for developmental cycle stages, gene expression regulatory factors, type III secretion system and their effectors, and individual virulence factors with known impacts.

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“…These characteristics makes Drosophila a valuable tool to discover new or underappreciated functions of bacterial effectors, particularly outside the confounding effects of infection. This approach has been used to study effectors from Helicobacter ( Reid et al, 2012 ) and Chlamydia ( Shehat et al, 2021 ). Drosophila -derived cell lines have also been used to study the Yersinia effector YopJ ( Paquette et al, 2012 ).…”

Section: Discussionmentioning

confidence: 99%

The Chlamydia trachomatis Early Effector Tarp Outcompetes Fascin in Forming F-Actin Bundles In Vivo

Aranjuez

Kim

Jewett

2022

Front. Cell. Infect. Microbiol.

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The intracellular pathogen Chlamydia trachomatis secretes multiple early effectors into the host cell to promote invasion. A key early effector during host cell entry, Tarp (translocated actin-recruiting phosphoprotein) is comprised of multiple protein domains known to have roles in cell signaling, G-actin nucleation and F-actin bundle formation. In vitro, the actin bundles generated by Tarp are uncharacteristically flexible, however, in vivo, the biological significance of Tarp-mediated actin bundles remains unknown. We hypothesize that Tarp’s ability to generate unique actin bundles, in part, facilitates chlamydial entry into epithelial cells. To study the in vivo interaction between Tarp and F-actin, we transgenically expressed Tarp in Drosophila melanogaster tissues. Tarp expressed in Drosophila is phosphorylated and forms F-actin-enriched aggregates in tissues. To gain insight into the significance of Tarp actin bundles in vivo, we utilized the well-characterized model system of mechanosensory bristle development in Drosophila melanogaster. Tarp expression in wild type flies produced curved bristles, indicating a perturbation in F-actin dynamics during bristle development. Two F-actin bundlers, Singed/Fascin and Forked/Espin, are important for normal bristle shape. Surprisingly, Tarp expression in the bristles displaced Singed/Fascin away from F-actin bundles. Tarp’s competitive behavior against Fascin during F-actin bundling was confirmed in vitro. Loss of either singed or forked in flies leads to highly deformed bristles. Strikingly, Tarp partially rescued the loss of singed, reducing the severity of the bristle morphology defect. This work provides in vivo confirmation of Tarp’s F-actin bundling activity and further uncovers a competitive behavior against the host bundler Singed/Fascin during bundle assembly. Also, we demonstrate the utility of Drosophila melanogaster as an in vivo cell biological platform to study bacterial effector function.

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The Chlamydia trachomatis Tarp effector targets the Hippo pathway

Cited by 7 publications

References 29 publications

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

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

Molecular pathogenesis of Chlamydia trachomatis

The Chlamydia trachomatis Early Effector Tarp Outcompetes Fascin in Forming F-Actin Bundles In Vivo

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