EspM2 is a RhoA guanine nucleotide exchange factor

Arbeloa, Ana; Garnett, James A.; Lillington, James; Bulgin, Richard; Berger, Cédric N.; Lea, Susan M.; Matthews, Stephen; Frankel, Gad

doi:10.1111/j.1462-5822.2009.01423.x

Cited by 53 publications

(47 citation statements)

References 35 publications

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“…Moreover, although not similar in sequence, the chemical properties of the residues within the putative catalytic loop of SifA are comparable to those found in SopE (51). Nonetheless, despite its similarities with SopE and the ability to bind RhoA, no GEF activity has yet been demonstrated for SifA (4,51).…”

Section: Wxxxe Effectors: From Rho Gtpase Mimics To Rho Gtpase Gefsmentioning

confidence: 80%

See 1 more Smart Citation

Bacterial Guanine Nucleotide Exchange Factors SopE-Like and WxxxE Effectors

Bulgin¹,

Raymond²,

Garnett

et al. 2010

Infect Immun

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Subversion of Rho family small GTPases, which control actin dynamics, is a common infection strategy used by bacterial pathogens. In particular, Salmonella enterica serovar Typhimurium, Shigella flexneri, enteropathogenic Escherichia coli (EPEC), and enterohemorrhagic Escherichia coli (EHEC) translocate type III secretion system (T3SS) effector proteins to modulate the Rho GTPases RhoA, Cdc42, and Rac1, which trigger formation of stress fibers, filopodia, and lamellipodia/ruffles, respectively. The Salmonella effector SopE is a guanine nucleotide exchange factor (GEF) that activates Rac1 and Cdc42, which induce "the trigger mechanism of cell entry." Based on a conserved Trp-xxx-Glu motif, the T3SS effector proteins IpgB1 and IpgB2 of Shigella, SifA and SifB of Salmonella, and Map of EPEC and EHEC were grouped together into a WxxxE family; recent studies identified the T3SS EPEC and EHEC effectors EspM and EspT as new family members. Recent structural and functional studies have shown that representatives of the WxxxE effectors share with SopE a 3-D fold and GEF activity. In this minireview, we summarize contemporary findings related to the SopE and WxxxE GEFs in the context of their role in subverting general host cell signaling pathways and infection.Colonization, multiplication, and dissemination are the key steps of an infectious cycle. To persist within the hostile in vivo environments, bacterial pathogens utilize sophisticated virulence strategies to subvert and hijack cellular and systemic functions. A common infection strategy used by Gram-negative pathogens involves injection of virulence factors, known as effectors, by the type III secretion system (T3SS) from the bacterial cell directly into the eukaryotic cell (reviewed in reference 26). The injected effectors target different cellular compartments and subvert numerous signaling pathways for the benefit of the invaded or attached bacteria. Due to their essential role in the regulation of key cellular functions, Rho family small G proteins are common targets of T3SS bacterial effectors (reviewed in reference 23).To date, 22 members of the Rho GTPase family, belonging to the small GTPase protein superfamily, have been identified (54). Cdc42, Rac1, and RhoA, which trigger formation of filopodia, lamellipodia/ruffles, and stress fibers, respectively, are the best characterized (29). The Rho GTPases share a conserved structure, consisting of two flexible domains called switch I and switch II and a phosphate binding loop (P-loop), which together form a Mg 2ϩ -and nucleotide-binding pocket (reviewed in reference 22). The small GTPases are modified posttranscriptionally by the addition of a lipid moiety to the C terminus (farnesyl, geranyl, palmitoyl, or methyl), signaled by the carboxy-terminal CAAX motif (55), which targets them to different membranous compartments.The function of the small GTPases is strictly regulated. By binding the two switch domains and the lipid moiety, the guanine nucleotide dissociation inhibitors (GDIs) prevent membrane localizatio...

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Section: Wxxxe Effectors: From Rho Gtpase Mimics To Rho Gtpase Gefsmentioning

confidence: 80%

“…Two recent independent reports have shown that several WxxxE effectors are also Rho GTPase GEFs (4,36). First, Huang et al demonstrated that Map specifically binds nucleotide-free Cdc42 and is able to induce the release of GDP and the incorporation of GTP (36).…”

Section: Wxxxe Effectors: From Rho Gtpase Mimics To Rho Gtpase Gefsmentioning

confidence: 99%

Bacterial Guanine Nucleotide Exchange Factors SopE-Like and WxxxE Effectors

Bulgin¹,

Raymond²,

Garnett

et al. 2010

Infect Immun

Self Cite

View full text Add to dashboard Cite

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“…In addition, SifA can bind to RhoA in human HeLa cells [212], and an interaction of SifA with a Rho GTPase has also been found using the model organism Saccharomyces cerevisiae [216]. However, the ability of SifA to catalyze nucleotide exchange on RhoA has not been demonstrated [217]. Interestingly, SKIP also interacts, through its PH domain, with the late endosome GTPase Rab9.…”

Section: 5mentioning

confidence: 99%

Impact ofSalmonella entericaType III Secretion System Effectors on the Eukaryotic Host Cell

Ramos‐Morales

2012

ISRN Cell Biology

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Type III secretion systems are molecular machines used by many Gram-negative bacterial pathogens to inject proteins, known as effectors, directly into eukaryotic host cells. These proteins manipulate host signal transduction pathways and cellular processes to the pathogen's advantage. Salmonella enterica possesses two virulence-related type III secretion systems that deliver more than forty effectors. This paper reviews our current knowledge about the functions, biochemical activities, host targets, and impact on host cells of these effectors. First, the concerted action of effectors at the cellular level in relevant aspects of the interaction between Salmonella and its hosts is analyzed. Then, particular issues that will drive research in the field in the near future are discussed. Finally, detailed information about each individual effector is provided.

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“…Rho GTPases are targeted by many bacterial effector proteins, including Yersinia pseudotuberculosis YopE (30), Salmonella enterica serovar Typhimurium SopE (40), Vibrio cholerae RTX toxin (41), and Escherichia coli EspH (29), indicating this is a conserved target of bacterial pathogens (42). Bacterial virulence factors and toxins regulate Rho activity using at least one of three methods (42): (i) through indirect regulation of localization and activation by mimicking Rho GAPs, guanine nucleotide exchange factors (GEFs), or guanine nucleotide dissociation inhibitors (GDIs) (30,43); (ii) direct regulation through posttranslational modifications, including ADP-ribosylation (44), adenylation (45), deamidation (46), and glucosylation (47); (iii) or through targeting upstream regulators (29,48). Consequently these modifications affect Rho GTPase activity and ultimately impact host signaling pathways, resulting in inhibition of immune function or endocytosis, generating a more permissive host for the pathogen.…”

Section: Discussionmentioning

confidence: 99%

The Type IV Secretion System Effector Protein CirA Stimulates the GTPase Activity of RhoA and Is Required for Virulence in a Mouse Model of Coxiella burnetii Infection

et al. 2016

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bCoxiella burnetii, the etiological agent of Q fever in humans, is an intracellular pathogen that replicates in an acidified parasitophorous vacuole derived from host lysosomes. Generation of this replicative compartment requires effectors delivered into the host cell by the Dot/Icm type IVb secretion system. Several effectors crucial for C. burnetii intracellular replication have been identified, but the host pathways coopted by these essential effectors are poorly defined, and very little is known about how spacious vacuoles are formed and maintained. Here we demonstrate that the essential type IVb effector, CirA, stimulates GTPase activity of RhoA. Overexpression of CirA in mammalian cells results in cell rounding and stress fiber disruption, a phenotype that is rescued by overexpression of wild-type or constitutively active RhoA. Unlike other effector proteins that subvert Rho GTPases to modulate uptake, CirA is the first effector identified that is dispensable for uptake and instead recruits Rho GTPase to promote biogenesis of the bacterial vacuole. Collectively our results highlight the importance of CirA in coopting host Rho GTPases for establishment of Coxiella burnetii infection and virulence in mammalian cell culture and mouse models of infection.T he naturally obligate intracellular pathogen Coxiella burnetii is the causative agent of Q fever in humans. The agent's high infectivity, ease of spread by aerosols, and environmental stability have led to its classification as a category B select agent by the Centers for Disease Control and Prevention (1). The primary route of infection is through inhalation of contaminated aerosols, which typical results in acute Q fever, a debilitating flu-like illness that is generally self-limiting and readily resolves without antibiotic treatment. However, under some circumstances, persistent infection can lead to chronic Q fever that presents as endocarditis or hepatitis (1). While the number of reported cases of acute Q fever in the United States has been relatively low, a marked increase occurred in 1999 when Q fever became a reportable disease. A recent outbreak of Q fever in The Netherlands resulted in over 4,000 confirmed cases, with 20% of patients requiring hospitalization (2). The dramatic increase in reported cases suggests C. burnetii is an emerging pathogen and highlights our lack of understanding of C. burnetii virulence factors.Inhalation of C. burnetii by a mammalian host results in actindependent endocytosis and internalization in an early endosome. While numerous intracellular pathogens actively subvert the default endocytic pathway to establish a unique host-derived vacuole, C. burnetii generally follows the default trafficking pathway to establish a Coxiella-containing vacuole (CCV) derived from the host lysosomal network. Generation of this unique replicative compartment requires active bacterial protein synthesis which drives homotypic and heterotypic vesicle fusions associated with generation of a spacious CCV that occupies the majority of the hos...

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EspM2 is a RhoA guanine nucleotide exchange factor

Cited by 53 publications

References 35 publications

Bacterial Guanine Nucleotide Exchange Factors SopE-Like and WxxxE Effectors

Bacterial Guanine Nucleotide Exchange Factors SopE-Like and WxxxE Effectors

Impact ofSalmonella entericaType III Secretion System Effectors on the Eukaryotic Host Cell

The Type IV Secretion System Effector Protein CirA Stimulates the GTPase Activity of RhoA and Is Required for Virulence in a Mouse Model of Coxiella burnetii Infection

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