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Inhibition of WAVE Regulatory Complex Activation by a Bacterial Virulence Effector Counteracts Pathogen Phagocytosis.

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Humphreys, Daniel 
Singh, Vikash 
Koronakis, Vassilis  ORCID logo


To establish pathogenicity, bacteria must evade phagocytosis directed by remodeling of the actin cytoskeleton. We show that macrophages facilitate pathogen phagocytosis through actin polymerization mediated by the WAVE regulatory complex (WRC), small GTPases Arf and Rac1, and the Arf1 activator ARNO. To establish extracellular infections, enteropathogenic (EPEC) and enterohaemorrhagic (EHEC) Escherichia coli hijack the actin cytoskeleton by injecting virulence effectors into the host cell. Here, we find that the virulence effector EspG counteracts WRC-dependent phagocytosis, enabling EPEC and EHEC to remain extracellular. By reconstituting membrane-associated actin polymerization, we find that EspG disabled WRC activation through two mechanisms: EspG interaction with Arf6 blocked signaling to ARNO while EspG binding of Arf1 impeded collaboration with Rac1, thereby inhibiting WRC recruitment and activation. Investigating the mode of EspG interference revealed sites in Arf1 required for WRC activation and a mechanism facilitating pathogen evasion of innate host defenses.



ADP-ribosylation factor, Rho GTPase, SCAR complex, type 3 secretion system, virulence effector, ADP-Ribosylation Factor 1, ADP-Ribosylation Factor 6, ADP-Ribosylation Factors, Enteropathogenic Escherichia coli, Escherichia coli Proteins, HeLa Cells, Humans, Models, Biological, Multiprotein Complexes, Phagocytosis, Salmonella, Signal Transduction, Virulence Factors, rac1 GTP-Binding Protein

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Elsevier BV
Medical Research Council (MR/L008122/1)
Medical Research Council (MR/M011771/1)
Wellcome Trust (101828/Z/13/Z)
This work was funded by the Wellcome Trust, Medical Research Council and the Cambridge Isaac Newton Trust. V.K. and D.H. thank the Wellcome Trust for funding of a Senior Investigator Award to V.K. (101828/Z/13/Z), the MRC for a research grant to V.K. (MR/L008122/1), and a New Investigator Research Grant to D.H. (MR/M011771/1).