The Arf GTPase-Activating Protein Family Is Exploited by <named-content content-type="genus-species">Salmonella enterica</named-content> Serovar Typhimurium To Invade Nonphagocytic Host Cells

ABSTRACT To establish intracellular infections, Salmonella bacteria trigger host cell membrane ruffling and invasion by subverting cellular Arf guanine nucleotide exchange factors (GEFs) that activate Arf1 and Arf6 GTPases by promoting GTP binding. A family of cellular Arf GTPase-activating proteins...

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Autores principales:	Anthony C. Davidson, Daniel Humphreys, Andrew B. E. Brooks, Peter J. Hume, Vassilis Koronakis
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2015
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/d3438ea1bd3d4b8da844642b3c3ac5ac
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spelling	oai:doaj.org-article:d3438ea1bd3d4b8da844642b3c3ac5ac2021-11-15T15:41:18ZThe Arf GTPase-Activating Protein Family Is Exploited by <named-content content-type="genus-species">Salmonella enterica</named-content> Serovar Typhimurium To Invade Nonphagocytic Host Cells10.1128/mBio.02253-142150-7511https://doaj.org/article/d3438ea1bd3d4b8da844642b3c3ac5ac2015-02-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02253-14https://doaj.org/toc/2150-7511ABSTRACT To establish intracellular infections, Salmonella bacteria trigger host cell membrane ruffling and invasion by subverting cellular Arf guanine nucleotide exchange factors (GEFs) that activate Arf1 and Arf6 GTPases by promoting GTP binding. A family of cellular Arf GTPase-activating proteins (GAPs) can downregulate Arf signaling by stimulating GTP hydrolysis, but whether they do this during infection is unknown. Here, we uncovered a remarkable role for distinct Arf GAP family members in Salmonella invasion. The Arf6 GAPs ACAP1 and ADAP1 and the Arf1 GAP ASAP1 localized at Salmonella-induced ruffles, which was not the case for the plasma membrane-localized Arf6 GAPs ARAP3 and GIT1 or the Golgi-associated Arf1 GAP1. Surprisingly, we found that loss of ACAP1, ADAP1, or ASAP1 impaired Salmonella invasion, revealing that GAPs cannot be considered mere terminators of cytoskeleton remodeling. Salmonella invasion was restored in Arf GAP-depleted cells by expressing fast-cycling Arf derivatives, demonstrating that Arf GTP/GDP cycles facilitate Salmonella invasion. Consistent with this view, both constitutively active and dominant-negative Arf derivatives that cannot undergo GTP/GDP cycles inhibited invasion. Furthermore, we demonstrated that Arf GEFs and GAPs colocalize at invading Salmonella and collaborate to drive Arf1-dependent pathogen invasion. This study revealed that Salmonella bacteria exploit a remarkable interplay between Arf GEFs and GAPs to direct cycles of Arf GTPase activation and inactivation. These cycles drive Salmonella cytoskeleton remodeling and enable intracellular infections. IMPORTANCE To initiate infections, the Salmonella bacterial pathogen remodels the mammalian actin cytoskeleton and invades host cells by subverting host Arf GEFs that activate Arf1 and Arf6 GTPases. Cellular Arf GAPs deactivate Arf GTPases and negatively regulate cell processes, but whether they target Arfs during infection is unknown. Here, we uncovered an important role for the Arf GAP family in Salmonella invasion. Surprisingly, we found that Arf1 and Arf6 GAPs cooperate with their Arf GEF counterparts to facilitate cycles of Arf GTPase activation and inactivation, which direct pathogen invasion. This report illustrates that GAP proteins promote actin-dependent processes and are not necessarily restricted to negatively regulating cellular signaling. It uncovers a remarkable interplay between Arf GEFs and GAPs that is exploited by Salmonella to establish infection and expands our understanding of Arf GTPase-regulated cytoskeleton remodeling.Anthony C. DavidsonDaniel HumphreysAndrew B. E. BrooksPeter J. HumeVassilis KoronakisAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 6, Iss 1 (2015)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Anthony C. Davidson Daniel Humphreys Andrew B. E. Brooks Peter J. Hume Vassilis Koronakis The Arf GTPase-Activating Protein Family Is Exploited by <named-content content-type="genus-species">Salmonella enterica</named-content> Serovar Typhimurium To Invade Nonphagocytic Host Cells
description	ABSTRACT To establish intracellular infections, Salmonella bacteria trigger host cell membrane ruffling and invasion by subverting cellular Arf guanine nucleotide exchange factors (GEFs) that activate Arf1 and Arf6 GTPases by promoting GTP binding. A family of cellular Arf GTPase-activating proteins (GAPs) can downregulate Arf signaling by stimulating GTP hydrolysis, but whether they do this during infection is unknown. Here, we uncovered a remarkable role for distinct Arf GAP family members in Salmonella invasion. The Arf6 GAPs ACAP1 and ADAP1 and the Arf1 GAP ASAP1 localized at Salmonella-induced ruffles, which was not the case for the plasma membrane-localized Arf6 GAPs ARAP3 and GIT1 or the Golgi-associated Arf1 GAP1. Surprisingly, we found that loss of ACAP1, ADAP1, or ASAP1 impaired Salmonella invasion, revealing that GAPs cannot be considered mere terminators of cytoskeleton remodeling. Salmonella invasion was restored in Arf GAP-depleted cells by expressing fast-cycling Arf derivatives, demonstrating that Arf GTP/GDP cycles facilitate Salmonella invasion. Consistent with this view, both constitutively active and dominant-negative Arf derivatives that cannot undergo GTP/GDP cycles inhibited invasion. Furthermore, we demonstrated that Arf GEFs and GAPs colocalize at invading Salmonella and collaborate to drive Arf1-dependent pathogen invasion. This study revealed that Salmonella bacteria exploit a remarkable interplay between Arf GEFs and GAPs to direct cycles of Arf GTPase activation and inactivation. These cycles drive Salmonella cytoskeleton remodeling and enable intracellular infections. IMPORTANCE To initiate infections, the Salmonella bacterial pathogen remodels the mammalian actin cytoskeleton and invades host cells by subverting host Arf GEFs that activate Arf1 and Arf6 GTPases. Cellular Arf GAPs deactivate Arf GTPases and negatively regulate cell processes, but whether they target Arfs during infection is unknown. Here, we uncovered an important role for the Arf GAP family in Salmonella invasion. Surprisingly, we found that Arf1 and Arf6 GAPs cooperate with their Arf GEF counterparts to facilitate cycles of Arf GTPase activation and inactivation, which direct pathogen invasion. This report illustrates that GAP proteins promote actin-dependent processes and are not necessarily restricted to negatively regulating cellular signaling. It uncovers a remarkable interplay between Arf GEFs and GAPs that is exploited by Salmonella to establish infection and expands our understanding of Arf GTPase-regulated cytoskeleton remodeling.
format	article
author	Anthony C. Davidson Daniel Humphreys Andrew B. E. Brooks Peter J. Hume Vassilis Koronakis
author_facet	Anthony C. Davidson Daniel Humphreys Andrew B. E. Brooks Peter J. Hume Vassilis Koronakis
author_sort	Anthony C. Davidson
title	The Arf GTPase-Activating Protein Family Is Exploited by <named-content content-type="genus-species">Salmonella enterica</named-content> Serovar Typhimurium To Invade Nonphagocytic Host Cells
title_short	The Arf GTPase-Activating Protein Family Is Exploited by <named-content content-type="genus-species">Salmonella enterica</named-content> Serovar Typhimurium To Invade Nonphagocytic Host Cells
title_full	The Arf GTPase-Activating Protein Family Is Exploited by <named-content content-type="genus-species">Salmonella enterica</named-content> Serovar Typhimurium To Invade Nonphagocytic Host Cells
title_fullStr	The Arf GTPase-Activating Protein Family Is Exploited by <named-content content-type="genus-species">Salmonella enterica</named-content> Serovar Typhimurium To Invade Nonphagocytic Host Cells
title_full_unstemmed	The Arf GTPase-Activating Protein Family Is Exploited by <named-content content-type="genus-species">Salmonella enterica</named-content> Serovar Typhimurium To Invade Nonphagocytic Host Cells
title_sort	arf gtpase-activating protein family is exploited by <named-content content-type="genus-species">salmonella enterica</named-content> serovar typhimurium to invade nonphagocytic host cells
publisher	American Society for Microbiology
publishDate	2015
url	https://doaj.org/article/d3438ea1bd3d4b8da844642b3c3ac5ac
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The Arf GTPase-Activating Protein Family Is Exploited by <named-content content-type="genus-species">Salmonella enterica</named-content> Serovar Typhimurium To Invade Nonphagocytic Host Cells

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