The Chlamydia Effector TarP Mimics the Mammalian Leucine-Aspartic Acid Motif of Paxillin to Subvert the Focal Adhesion Kinase during Invasion

Thwaites, Tristan R.; Nogueira, Ana T.; Campeotto, Ivan; Silva, Ana Paula; Grieshaber, Scott S.; Carabeo, Rey A.

doi:10.1074/jbc.m114.604876

Cited by 32 publications

(57 citation statements)

References 53 publications

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“…Conversely, many unique characteristics, such as C. trachomatis L2 Tarp phosphorylation or C. caviae strain GPIC Tarp's ability to bind to focal adhesion kinase (FAK) reveal that Tarp orthologs may have evolved to serve specific functions for unique human versus animal hosts (Clifton et al, 2005; Thwaites et al, 2014). The ability to introduce Tarp deletion mutants into C. trachomatis is the first step toward defining which protein domains may play a dominant role in vivo .…”

Section: Discussionmentioning

confidence: 99%

Targeted Disruption of Chlamydia trachomatis Invasion by in Trans Expression of Dominant Negative Tarp Effectors

Parrett

Lenoci

Nguyen

et al. 2016

Front. Cell. Infect. Microbiol.

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Chlamydia trachomatis invasion of eukaryotic host cells is facilitated, in part, by the type III secreted effector protein, Tarp. The role of Tarp in chlamydiae entry of host cells is supported by molecular approaches that examined recombinant Tarp or Tarp effectors expressed within heterologous systems. A major limitation in the ability to study the contribution of Tarp to chlamydial invasion of host cells was the prior absence of genetic tools for chlamydiae. Based on our knowledge of Tarp domain structure and function along with the introduction of genetic approaches in C. trachomatis , we hypothesized that Tarp function could be disrupted in vivo by the introduction of dominant negative mutant alleles. We provide evidence that transformed C. trachomatis produced epitope tagged Tarp, which was secreted into the host cell during invasion. We examined the effects of domain specific Tarp mutations on chlamydial invasion and growth and demonstrate that C. trachomatis clones harboring engineered Tarp mutants lacking either the actin binding domain or the phosphorylation domain had reduced levels of invasion into host cells. These data provide the first in vivo evidence for the critical role of Tarp in C. trachomatis pathogenesis and indicate that chlamydial invasion of host cells can be attenuated via the introduction of engineered dominant negative type three effectors.

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Section: Discussionmentioning

confidence: 99%

Targeted Disruption of Chlamydia trachomatis Invasion by in Trans Expression of Dominant Negative Tarp Effectors

Parrett

Lenoci

Nguyen

et al. 2016

Front. Cell. Infect. Microbiol.

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“…Translocated actin-recruiting phosphoprotein (TarP; also known as CT456) is a multidomain protein that nucleates and bundles actin through its own globular actin (G-actin) and filamentous actin (F-actin) domains and is thought to synergize with the host ARP2/3 complex 16,43 . In addition, TarP in C. caviae contains a mammalian leucine–aspartic acid (LD2)-like motif that subverts focal adhesion kinase (FAK) signalling 44 . Some TarP orthologues contain an amino-terminal domain with 1–9 tyrosine-containing repeats, which are phosphorylated by ABL and SRC-family tyrosine kinases (SFKs) 16 .…”

Section: Binding and Invasionmentioning

confidence: 99%

Chlamydia cell biology and pathogenesis

2016

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Chlamydia spp. are important causes of human disease for which no effective vaccine exists. These obligate intracellular pathogens replicate in a specialized membrane compartment and use a large arsenal of secreted effectors to survive in the hostile intracellular environment of the host. In this Review, we summarize the progress in decoding the interactions between Chlamydia spp. and their hosts that has been made possible by recent technological advances in chlamydial proteomics and genetics. The field is now poised to decipher the molecular mechanisms that underlie the intimate interactions between Chlamydia spp. and their hosts, which will open up many exciting avenues of research for these medically important pathogens.

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“…The chlamydial type III effector TarP has been implicated in the invasion process during infection of non-phagocytic cells. Specifically, TarP translocation by the elementary bodies contributes to the actin remodeling that is required for uptake of the pathogen (Clifton et al ., 2005; Jewett et al ., 2006; Lane et al ., 2008; Thwaites et al ., 2014). Interestingly, TarP was also reported to have a role in increased resistance of infected cells to apoptosis, raising the possibility that this effector has post-invasion function (Mehlitz et al ., 2010).…”

Section: Resultsmentioning

confidence: 99%

“…2010; Mehlitz et al . 2010; Jiwani et al ., 2013; Thwaites et al ., 2014, 2015; Braun et al ., 2019). All have been demonstrated in invasion-related actin-recruitment assays to be functional(Lane et al ., 2008; Thwaites et al ., 2014, 2015).…”

Section: Resultsmentioning

confidence: 99%

“…2010; Jiwani et al ., 2013; Thwaites et al ., 2014, 2015; Braun et al ., 2019). All have been demonstrated in invasion-related actin-recruitment assays to be functional(Lane et al ., 2008; Thwaites et al ., 2014, 2015). We created various C-terminal deletion constructs of TarP fused to mTurquoise for heterologous expression in MEFs, as well as a TarP derivative lacking the proline-rich domain (PRD) to minimize non-specific aggregation of the protein.…”

Section: Resultsmentioning

confidence: 99%

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The Chlamydia type III effector TarP alters the dynamics and organization of host cell focal adhesions

Pedrosa

Nogueira

Thwaites

et al. 2018

Preprint

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29The human pathogen Chlamydia trachomatis targets epithelial cells lining the genital mucosa. 30We observed that infection of various cell types, including fibroblasts and epithelial cells resulted 31 in the formation of unusually stable focal adhesions that resisted disassembly induced by the 32 myosin II inhibitor, blebbistatin. Super-resolution microscopy revealed in infected cells the 33 vertical displacement of paxillin and FAK from the signaling layer of focal adhesions; while 34 vinculin remained in its normal position within the force transduction layer. The candidate type III 35 effector TarP which localized to focal adhesions during infection and when expressed 36 ectopically, was sufficient to mimic both the reorganization and blebbistatin-resistant 37 phenotypes. These effects of TarP, including its localization to focal adhesions required 38 interaction with the host protein vinculin through a specific domain at the C-terminus of TarP. 39The consequence of Chlamydia-stabilized focal adhesions was restricted cell motility and 40 enhanced attachment to the extracellular matrix. Thus, via a novel mechanism, Chlamydia 41 inserts TarP within focal adhesions to alter their organization and dynamics. 48attachment to the extracellular matrix, and their assembly and turnover are exquisitely regulated 49 at multiple levels, by kinases, phosphatases, protein-protein interactions, internalization of 50 components, and degradation (Borradori and Sonnenberg, 1999; Geiger et al., 2001; Rosenblatt 51 et al., 2001; Zaidel-Bar et al., 2007). Disruption of one or more of these regulatory processes 52 alters the adhesion dynamics and properties of the cells. 53One strategy employed by bacteria to neutralize exfoliation relies on the precise 54 targeting of one or more components of the focal adhesion proteome. The best-characterized 55 example is that of Shigella, which neutralizes epithelial extrusion to colonize the epithelium 56 efficiently (Kim et al., 2009). It does so by delivering the OspE effector by the type III secretion 57 system (T3SS). This protein reinforces host cell adherence to the basement membrane by 58 interacting with integrin-linked kinase (ILK), a serine/threonine kinase that is part of the focal 59 adhesome (Kim et al., 2009; Zaidel-Bar et al., 2007). A consequence of the OspE-ILK 60 interaction is an increased surface expression of β1-integrin, which in turn promotes focal 61 adhesion (FA) assembly. In addition, the OspE-ILK complex stabilizes the focal adhesions (FAs) 62 by reducing phosphorylation of focal adhesion kinase (FAK) at a functionally important Tyr397 63 residue and of paxillin. Inhibition of both phosphorylation events has been shown to induce FA 64 disassembly (Kim et al., 2009). Interestingly, some EPEC and EHEC strains, as well as 65 Citrobacter rodentium possess the effector EspO, which shares strong homology with OspE 66 (reviewed in Vossenkämper, Macdonald and Marchès, 2011; Morita-Ishihara et al., 2013). As 67 such, it is conceivable that these pathogens also reinforce ...

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The Chlamydia Effector TarP Mimics the Mammalian Leucine-Aspartic Acid Motif of Paxillin to Subvert the Focal Adhesion Kinase during Invasion

Cited by 32 publications

References 53 publications

Targeted Disruption of Chlamydia trachomatis Invasion by in Trans Expression of Dominant Negative Tarp Effectors

Targeted Disruption of Chlamydia trachomatis Invasion by in Trans Expression of Dominant Negative Tarp Effectors

Chlamydia cell biology and pathogenesis

The Chlamydia type III effector TarP alters the dynamics and organization of host cell focal adhesions

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