Inhibition of WAVE Regulatory Complex Activation by a Bacterial Virulence Effector Counteracts Pathogen Phagocytosis
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...
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doaj-bb4a8ae99fac4945afe408b3cf76d7832020-11-25T02:13:28ZengElsevierCell Reports2211-12472016-10-0117369770710.1016/j.celrep.2016.09.039Inhibition of WAVE Regulatory Complex Activation by a Bacterial Virulence Effector Counteracts Pathogen PhagocytosisDaniel Humphreys0Vikash Singh1Vassilis Koronakis2Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QP, UKDepartment of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QP, UKDepartment of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QP, UKTo 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.http://www.sciencedirect.com/science/article/pii/S2211124716312785SCAR complexRho GTPasevirulence effectortype 3 secretion systemADP-ribosylation factor |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Daniel Humphreys Vikash Singh Vassilis Koronakis |
spellingShingle |
Daniel Humphreys Vikash Singh Vassilis Koronakis Inhibition of WAVE Regulatory Complex Activation by a Bacterial Virulence Effector Counteracts Pathogen Phagocytosis Cell Reports SCAR complex Rho GTPase virulence effector type 3 secretion system ADP-ribosylation factor |
author_facet |
Daniel Humphreys Vikash Singh Vassilis Koronakis |
author_sort |
Daniel Humphreys |
title |
Inhibition of WAVE Regulatory Complex Activation by a Bacterial Virulence Effector Counteracts Pathogen Phagocytosis |
title_short |
Inhibition of WAVE Regulatory Complex Activation by a Bacterial Virulence Effector Counteracts Pathogen Phagocytosis |
title_full |
Inhibition of WAVE Regulatory Complex Activation by a Bacterial Virulence Effector Counteracts Pathogen Phagocytosis |
title_fullStr |
Inhibition of WAVE Regulatory Complex Activation by a Bacterial Virulence Effector Counteracts Pathogen Phagocytosis |
title_full_unstemmed |
Inhibition of WAVE Regulatory Complex Activation by a Bacterial Virulence Effector Counteracts Pathogen Phagocytosis |
title_sort |
inhibition of wave regulatory complex activation by a bacterial virulence effector counteracts pathogen phagocytosis |
publisher |
Elsevier |
series |
Cell Reports |
issn |
2211-1247 |
publishDate |
2016-10-01 |
description |
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. |
topic |
SCAR complex Rho GTPase virulence effector type 3 secretion system ADP-ribosylation factor |
url |
http://www.sciencedirect.com/science/article/pii/S2211124716312785 |
work_keys_str_mv |
AT danielhumphreys inhibitionofwaveregulatorycomplexactivationbyabacterialvirulenceeffectorcounteractspathogenphagocytosis AT vikashsingh inhibitionofwaveregulatorycomplexactivationbyabacterialvirulenceeffectorcounteractspathogenphagocytosis AT vassiliskoronakis inhibitionofwaveregulatorycomplexactivationbyabacterialvirulenceeffectorcounteractspathogenphagocytosis |
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1724905030975225856 |