EPEC Recruits a Cdc42-Specific GEF, Frabin, To Facilitate PAK Activation and Host Cell Colonization

ABSTRACT Enteropathogenic Escherichia coli (EPEC) is an extracellular pathogen that tightly adheres to host cells by forming “actin pedestals” beneath the bacteria, a critical step in pathogenesis. EPEC injects effector proteins that manipulate host cell signaling cascades to trigger pedestal assemb...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Vikash Singh, Peter J. Hume, Anthony Davidson, Vassilis Koronakis
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	EPEC EspG GTPases actin Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/7e27a2ed99ff406f9ea742c2ce9ed96f
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:7e27a2ed99ff406f9ea742c2ce9ed96f
record_format	dspace
spelling	oai:doaj.org-article:7e27a2ed99ff406f9ea742c2ce9ed96f2021-11-15T15:55:43ZEPEC Recruits a Cdc42-Specific GEF, Frabin, To Facilitate PAK Activation and Host Cell Colonization10.1128/mBio.01423-202150-7511https://doaj.org/article/7e27a2ed99ff406f9ea742c2ce9ed96f2020-12-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01423-20https://doaj.org/toc/2150-7511ABSTRACT Enteropathogenic Escherichia coli (EPEC) is an extracellular pathogen that tightly adheres to host cells by forming “actin pedestals” beneath the bacteria, a critical step in pathogenesis. EPEC injects effector proteins that manipulate host cell signaling cascades to trigger pedestal assembly. We have recently shown that one such effector, EspG, hijacks p21-activated kinase (PAK) and sustains its activated state to drive the cytoskeletal changes necessary for attachment of the pathogen to target cells. This EspG subversion of PAK required active Rho family small GTPases in the host cell. Here we show that EPEC itself promotes the activation of Rho GTPases by recruiting Frabin, a host guanine nucleotide exchange factor (GEF) for the Rho GTPase Cdc42. Cells devoid of Frabin showed significantly lower EPEC-induced PAK activation, pedestal formation, and bacterial attachment. Frabin recruitment to sites of EPEC attachment was driven by EspG and required localized enrichment of phosphatidylinositol 4,5-bisphosphate (PIP2) and host Arf6. Our findings identify Frabin as a key target for EPEC to ensure the activation status of cellular GTPases required for actin pedestal formation. IMPORTANCE Enteropathogenic Escherichia coli (EPEC) is a leading cause of diarrhea in children, especially in the developing world. EPEC initiates infection by attaching to cells in the host intestine, triggering the formation of actin-rich “pedestal” structures directly beneath the adherent pathogen. These bacteria inject their own receptor into host cells, which upon binding to a protein on the pathogen surface triggers pedestal formation. Multiple other proteins are also delivered into the cells of the host intestine, which work together to hijack host signaling pathways to drive pedestal production. Here we show how EPEC hijacks a host protein, Frabin, which creates the conditions in the cell necessary for the pathogen to manipulate a specific pathway that promotes pedestal formation. This provides new insights into this essential early stage in disease caused by EPEC.Vikash SinghPeter J. HumeAnthony DavidsonVassilis KoronakisAmerican Society for MicrobiologyarticleEPECEspGGTPasesactinMicrobiologyQR1-502ENmBio, Vol 11, Iss 6 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	EPEC EspG GTPases actin Microbiology QR1-502
spellingShingle	EPEC EspG GTPases actin Microbiology QR1-502 Vikash Singh Peter J. Hume Anthony Davidson Vassilis Koronakis EPEC Recruits a Cdc42-Specific GEF, Frabin, To Facilitate PAK Activation and Host Cell Colonization
description	ABSTRACT Enteropathogenic Escherichia coli (EPEC) is an extracellular pathogen that tightly adheres to host cells by forming “actin pedestals” beneath the bacteria, a critical step in pathogenesis. EPEC injects effector proteins that manipulate host cell signaling cascades to trigger pedestal assembly. We have recently shown that one such effector, EspG, hijacks p21-activated kinase (PAK) and sustains its activated state to drive the cytoskeletal changes necessary for attachment of the pathogen to target cells. This EspG subversion of PAK required active Rho family small GTPases in the host cell. Here we show that EPEC itself promotes the activation of Rho GTPases by recruiting Frabin, a host guanine nucleotide exchange factor (GEF) for the Rho GTPase Cdc42. Cells devoid of Frabin showed significantly lower EPEC-induced PAK activation, pedestal formation, and bacterial attachment. Frabin recruitment to sites of EPEC attachment was driven by EspG and required localized enrichment of phosphatidylinositol 4,5-bisphosphate (PIP2) and host Arf6. Our findings identify Frabin as a key target for EPEC to ensure the activation status of cellular GTPases required for actin pedestal formation. IMPORTANCE Enteropathogenic Escherichia coli (EPEC) is a leading cause of diarrhea in children, especially in the developing world. EPEC initiates infection by attaching to cells in the host intestine, triggering the formation of actin-rich “pedestal” structures directly beneath the adherent pathogen. These bacteria inject their own receptor into host cells, which upon binding to a protein on the pathogen surface triggers pedestal formation. Multiple other proteins are also delivered into the cells of the host intestine, which work together to hijack host signaling pathways to drive pedestal production. Here we show how EPEC hijacks a host protein, Frabin, which creates the conditions in the cell necessary for the pathogen to manipulate a specific pathway that promotes pedestal formation. This provides new insights into this essential early stage in disease caused by EPEC.
format	article
author	Vikash Singh Peter J. Hume Anthony Davidson Vassilis Koronakis
author_facet	Vikash Singh Peter J. Hume Anthony Davidson Vassilis Koronakis
author_sort	Vikash Singh
title	EPEC Recruits a Cdc42-Specific GEF, Frabin, To Facilitate PAK Activation and Host Cell Colonization
title_short	EPEC Recruits a Cdc42-Specific GEF, Frabin, To Facilitate PAK Activation and Host Cell Colonization
title_full	EPEC Recruits a Cdc42-Specific GEF, Frabin, To Facilitate PAK Activation and Host Cell Colonization
title_fullStr	EPEC Recruits a Cdc42-Specific GEF, Frabin, To Facilitate PAK Activation and Host Cell Colonization
title_full_unstemmed	EPEC Recruits a Cdc42-Specific GEF, Frabin, To Facilitate PAK Activation and Host Cell Colonization
title_sort	epec recruits a cdc42-specific gef, frabin, to facilitate pak activation and host cell colonization
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/7e27a2ed99ff406f9ea742c2ce9ed96f
work_keys_str_mv	AT vikashsingh epecrecruitsacdc42specificgeffrabintofacilitatepakactivationandhostcellcolonization AT peterjhume epecrecruitsacdc42specificgeffrabintofacilitatepakactivationandhostcellcolonization AT anthonydavidson epecrecruitsacdc42specificgeffrabintofacilitatepakactivationandhostcellcolonization AT vassiliskoronakis epecrecruitsacdc42specificgeffrabintofacilitatepakactivationandhostcellcolonization
_version_	1718427157781282816

EPEC Recruits a Cdc42-Specific GEF, Frabin, To Facilitate PAK Activation and Host Cell Colonization

Ejemplares similares