Journal
CELL REPORTS
Volume 17, Issue 3, Pages 697-707Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2016.09.039
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Funding
- Wellcome Trust
- Medical Research Council
- Cambridge Isaac Newton Trust
- Wellcome Trust [101828/Z/13/Z]
- MRC [MR/L008122/1, MR/M011771/1]
- Wellcome Trust [101828/Z/13/Z] Funding Source: Wellcome Trust
- MRC [MR/L008122/1, MR/M011771/1, MR/M011771/2] Funding Source: UKRI
- Medical Research Council [MR/L008122/1, MR/M011771/1, MR/M011771/2] Funding Source: researchfish
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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.
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