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

Humphreys, Daniel; Singh, Vikash; Koronakis, Vassilis

doi:10.1016/j.celrep.2016.09.039

Cited by 29 publications

(37 citation statements)

References 50 publications

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“…Previously, a number of studies [17][18][19] have indicated the involvement of both Arf6 and Arf1 in controlling phagocytosis by regulating actin assembly. Furthermore, we have previously shown [20] that Arf1 achieves this by directly mediating WRC actin polymerization, which was crucial for the phagocytosis of pathogenic E. coli. Thus, we next examined whether the Arf6-and Rac1-dependent WRC recruitment had any effect on phagocytosis.…”

Section: Arf6 Regulates Phagocytosis In Differentiated Thp-1 Human Mamentioning

confidence: 97%

Arf6 Can Trigger Wave Regulatory Complex-Dependent Actin Assembly Independent of Arno

Singh

Davidson

Hume

et al. 2020

IJMS

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The small GTPase ADP-ribosylation factor 6 (Arf6) anchors at the plasma membrane to orchestrate key functions, such as membrane trafficking and regulating cortical actin cytoskeleton rearrangement. A number of studies have identified key players that interact with Arf6 to regulate actin dynamics in diverse cell processes, yet it is still unknown whether Arf6 can directly signal to the wave regulatory complex to mediate actin assembly. By reconstituting actin dynamics on supported lipid bilayers, we found that Arf6 in co-ordination with Rac1(Ras-related C3 botulinum toxin substrate 1) can directly trigger actin polymerization by recruiting wave regulatory complex components. Interestingly, we demonstrated that Arf6 triggers actin assembly at the membrane directly without recruiting the Arf guanine nucleotide exchange factor (GEF) ARNO (ARF nucleotide-binding site opener), which is able to activate Arf1 to enable WRC-dependent actin assembly. Furthermore, using labelled E. coli, we demonstrated that actin assembly by Arf6 also contributes towards efficient phagocytosis in THP-1 macrophages. Taken together, this study reveals a mechanism for Arf6-driven actin polymerization.

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Section: Arf6 Regulates Phagocytosis In Differentiated Thp-1 Human Mamentioning

confidence: 97%

Arf6 Can Trigger Wave Regulatory Complex-Dependent Actin Assembly Independent of Arno

Singh

Davidson

Hume

et al. 2020

IJMS

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“…EspG also alters paracellular permeability via modulation of tight junctions, although the mechanism of this is unclear at present (113,114). In macrophages, EspG prevents phagocytosis of attached bacteria by binding to ARF6 and ARF1, ultimately preventing the WAVE-dependent Arp2/3-mediated actin polymerisation necessary for efficient uptake of the bacteria into the macrophage (115).…”

Section: Espg Manipulates Cell-cell Contacts and The Host Cell Surfacementioning

confidence: 99%

Modulation of Host Cell Processes by T3SS Effectors

Shenoy

Furniss

Goddard

et al. 2018

Current Topics in Microbiology and Immunology

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Two of the enteric Escherichia coli pathotypes-enteropathogenic E. coli (EPEC) and enterohaemorrhagic E. coli (EHEC)-have a conserved type 3 secretion system which is essential for virulence. The T3SS is used to translocate between 25 and 50 bacterial proteins directly into the host cytosol where they manipulate a variety of host cell processes to establish a successful infection. In this chapter, we discuss effectors from EPEC/EHEC in the context of the host proteins and processes that they target-the actin cytoskeleton, small guanosine triphosphatases and innate immune signalling pathways that regulate inflammation and cell death. Many of these translocated proteins have been extensively characterised, which has helped obtain insights into the mechanisms of pathogenesis of these bacteria and also understand the host pathways they target in more detail. With increasing knowledge of the positive and negative regulation of host signalling pathways by different effectors, a future challenge is to investigate how the specific effector repertoire of each strain cooperates over the course of an infection.

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“…44 Phagocytosis in part is driven via WRC dependent actin assembly, a process that requires cooperating Arf and Rac1 GTPases. 45 In an attempt to evade this process EPEC likely interferes with one or more of these components. The effector protein EspG, know to interact with Arf1 was thus an intriguing candidate to investigate.…”

Section: Escherichia Coli Interfere With Arf Signaling To Block Wave mentioning

confidence: 99%

“…47,48 EspG was found to incapacitate WRC activation via a dual mechanism. 45 Firstly, EspG binding to Arf1 impedes cooperation with Rac1, thereby inhibiting WRC recruitment and activation. Further investigation of the mechanism by which EspG incapacitates WRC, identified key residues in the Arf1 a¡1 helix and switch-1 domain, which might be critical for WRC activation.…”

Section: Escherichia Coli Interfere With Arf Signaling To Block Wave mentioning

confidence: 99%

“…Further investigation of the mechanism by which EspG incapacitates WRC, identified key residues in the Arf1 a¡1 helix and switch-1 domain, which might be critical for WRC activation. In addition EspG's interaction with Arf6 sterically hinders its interaction with Arno, 45 thereby preventing Arf1 activation and consequent WRC-mediated phagocytosis. Another EPEC/ EHEC injected effector protein EspH has been previously shown to inhibit actin driven phagocytosis by disrupting the actin cytoskeleton.…”

Section: Escherichia Coli Interfere With Arf Signaling To Block Wave mentioning

confidence: 99%

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Arf GTPase interplay with Rho GTPases in regulation of the actin cytoskeleton

et al. 2017

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The Arf and Rho subfamilies of small GTPases are nucleotide-dependent molecular switches that act as master regulators of vesicular trafficking and the actin cytoskeleton organization. Small GTPases control cell processes with high fidelity by acting through distinct repertoires of binding partners called effectors. While we understand a great deal about how these GTPases act individually, relatively little is known about how they cooperate, especially in the control of effectors. This review highlights how Arf GTPases collaborate with Rac1 to regulate actin cytoskeleton dynamics at the membrane via recruiting and activating the Wave Regulatory Complex (WRC), a Rho effector that underpins lamellipodia formation and macropinocytosis. This provides insight into Arf regulation of the actin cytoskeleton, while putting the spotlight on small GTPase cooperation with emerging evidence of its importance in fundamental cell biology and interactions with pathogenic bacteria.

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

Cited by 29 publications

References 50 publications

Arf6 Can Trigger Wave Regulatory Complex-Dependent Actin Assembly Independent of Arno

Arf6 Can Trigger Wave Regulatory Complex-Dependent Actin Assembly Independent of Arno

Modulation of Host Cell Processes by T3SS Effectors

Arf GTPase interplay with Rho GTPases in regulation of the actin cytoskeleton

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