Abstract
Host cell signal transduction pathways are often targets of bacterial pathogens, especially during the process of invasion when robust actin remodeling is required. We demonstrate that the host cell focal adhesion kinase (FAK) was necessary for the invasion by the obligate intracellular pathogen Chlamydia caviae. Bacterial adhesion triggered the transient recruitment of FAK to the plasma membrane to mediate a Cdc42- and Arp2/3-dependent actin assembly. FAK recruitment was via binding to a domain within the virulence factor TarP that mimicked the LD2 motif of the FAK binding partner paxillin. Importantly, bacterial two-hybrid and quantitative imaging assays revealed a similar level of interaction between paxillin-LD2 and TarP-LD. The conserved leucine residues within the L(D/E)XLLXXL motif were essential to the recruitment of FAK, Cdc42, p34(Arc), and actin to the plasma membrane. In the absence of FAK, TarP-LD-mediated F-actin assembly was reduced, highlighting the functional relevance of this interaction. Together, the data indicate that a prokaryotic version of the paxillin LD2 domain targets the FAK signaling pathway, with TarP representing the first example of an LD-containing Type III virulence effector.
Highlights
Chlamydia signals to the actin cytoskeleton via its virulence factor TarP during invasion
The data indicate that a prokaryotic version of the paxillin LD2 domain targets the focal adhesion kinase (FAK) signaling pathway, with TarP representing the first example of an LD-containing Type III virulence effector
The FAK has been implicated in Chlamydia invasion, with Coombes and Mahony [21] first reporting its phospho-activation during infection by C. pneumoniae
Summary
Chlamydia signals to the actin cytoskeleton via its virulence factor TarP during invasion. Results: TarP contains a paxillin LD2-like motif that is recognized by the focal adhesion kinase (FAK) This interaction is required for signaling to the actin cytoskeleton. Chlamydiaceae have evolved to efficiently invade non-phagocytic epithelial cells utilizing the translocation of the type III effector TarP [15] This protein functions at the plasma membrane to mediate actin remodeling at the plasma membrane via host-signaling [16] and actin-nucleating activities [17], which cooperate to ensure efficient chlamydial uptake. Consistent with a signaling function, it was found that this chlamydial LD motif interacted directly with FAK to the same level as the LD2 motif of paxillin They recruited FAK, Cdc, and actin to the plasma membrane, indicative of similar biochemical properties. The data indicate that in addition to F-actin binding, this region of TarP that contains the LD motif functions in signaling, classifying TarP as the first Type III effector that mimics paxillin with regard to FAK binding
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