A Bacterial Guanine Nucleotide Exchange Factor Activates ARF on
            <i>Legionella</i>
            Phagosomes

Nagai, Hiroki; Kagan, Jonathan C.; Zhu, Xinjun; Kahn, Richard; Roy, Craig R.

doi:10.1126/science.1067025

Cited by 525 publications

(583 citation statements)

References 30 publications

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“…The genomes of Legionella and of Rickettsia encode a type IV effector with a Sec7 domain homologous to that of eukaryotic ArfGEFs which functions as a GEF to activate host Arf GTPases. 65 The structure of Legionella RalF showed that the Sec7 domain is strongly autoinhibited by a C-terminal domain that blocks access to the Arf-binding site, 66 and a similar autoinhibited conformation was observed in the Rickettsia RalF homolog. 67 Both bacterial ArfGEFs are strongly activated by membranes, and the membrane-binding site is identical to the elements in the autoinhibitory domain that blocks the Arf-binding site.…”

Section: Regulation Of Bacterial Arfgefs By Membranesmentioning

confidence: 89%

“…68,69 Thus, activation of Arf GTPases by RalF strictly depends on its recruitment to membranes. Legionella RalF produces Arf-GTP at the surface of the Legionella-containing vacuole where the pathogen hides and replicates; 65 however Rickettsia replicates in the host cytosol and therefore should use RalF for different functions. In that regard, it is remarkable that Legionella and Rickettsia RalF respond to different membrane characteristics for their activation.…”

Section: Regulation Of Bacterial Arfgefs By Membranesmentioning

confidence: 99%

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Allosteric regulation of Arf GTPases and their GEFs at the membrane interface

2016

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Arf GTPases assemble protein complexes on membranes to carry out major functions in cellular traffic. An essential step is their activation by guanine nucleotide exchange factors (GEFs), whose Sec7 domain stimulates GDP/GTP exchange. ArfGEFs form 2 major families: ArfGEFs with DCB, HUS and HDS domains (GBF1 and BIG1/BIG2 in humans), which act at the Golgi; and ArfGEFs with a Cterminal PH domain (cytohesin, EFA6 and BRAG), which function at the plasma membrane and endosomes. In addition, pathogenic bacteria encode an ArfGEF with a unique membrane-binding domain. Here we review the allosteric regulation of Arf GTPases and their GEFs at the membrane interface. Membranes contribute several regulatory layers: at the GTPase level, where activation by GTP is coupled to membrane recruitment by a built-in structural device; at the Sec7 domain, which manipulates this device to ensure that Arf-GTP is attached to membranes; and at the level of noncatalytic ArfGEF domains, which form direct or GTPase-mediated interactions with membranes that enable a spectacular diversity of regulatory regimes. Notably, we show here that membranes increase the efficiency of a large ArfGEF (human BIG1) by 32-fold by interacting directly with its Nterminal DCB and HUS domains. The diversity of allosteric regulatory regimes suggests that ArfGEFs can function in cascades and circuits to modulate the shape, amplitude and duration of Arf signals in cells. Because Arf-like GTPases feature autoinhibitory elements similar to those of Arf GTPases, we propose that their activation also requires allosteric interactions of these elements with membranes or other proteins.

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Section: Regulation Of Bacterial Arfgefs By Membranesmentioning

confidence: 89%

Section: Regulation Of Bacterial Arfgefs By Membranesmentioning

confidence: 99%

Allosteric regulation of Arf GTPases and their GEFs at the membrane interface

2016

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“…RalF is translocated through the phagosomal membrane where it recruits and activates ARF1, a member of the ADP RIBOSYLATION FACTOR family of guanosine triphosphatases (GTPases) to the phagosomal membrane. Although the function of ARF1 during infection is not yet defined, RalF recruitment and activation of ARF1 is postulated to enhance the efficiency of replicative vacuole formation 104 . As with the A. tumefaciens and H. pylori T4S systems, there are recent indications from several laboratories that the L. pneumophila Dot/Icm system might translocate additional effectors during its infection cycle.…”

Section: Pneumophila Dot/icm Substratesmentioning

confidence: 99%

The versatile bacterial type IV secretion systems

Cascales¹,

Christie²

2003

Nat Rev Microbiol

600

559

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Bacteria use type IV secretion systems for two fundamental objectives related to pathogenesisgenetic exchange and the delivery of effector molecules to eukaryotic target cells. Whereas gene acquisition is an important adaptive mechanism that enables pathogens to cope with a changing environment during invasion of the host, interactions between effector and host molecules can suppress defence mechanisms, facilitate intracellular growth and even induce the synthesis of nutrients that are beneficial to bacterial colonization. Rapid progress has been made towards defining the structures and functions of type IV secretion machines, identifying the effector molecules, and elucidating the mechanisms by which the translocated effectors subvert eukaryotic cellular processes during infection. The year 2003 marks the fiftieth anniversary of the first description of a TYPE IV SECRETION (T4S)SYSTEM: the CONJUGATION apparatus of the F plasmid 1 . This is a dynamic bacterial surface organelle, the activities of which are now known to include the contact-dependent delivery of DNA to bacterial recipients and the assembly and retraction of a conjugal PILUS 2 . In the past decade, reports describing systems that are ancestrally related to the F-transfer system and other conjugation machines have emerged. Instead of mediating DNA transfer between bacteria, these systems deliver DNA or protein substrates, known as effectors, to eukaryotic target cells during infection [3][4][5] . More recently, several new T4S systems have been described that are also ancestrally related to the conjugation machines, but these systems mediate the exchange of DNA with the extracellular milieu [6][7][8] . Collectively, this diversity of function in the face of a common ancestry makes the T4S machines attractive subjects for comparative studies that explore the dynamics of organelle assembly and action. Additionally, from a medical perspective, it is of enormous interest to develop a detailed understanding of how the inter-kingdom transfer of type IV effector molecules contributes to pathogenesis. This review will summarize the recent advances in our knowledge of T4S, NIH Public Access Author ManuscriptNat Rev Microbiol. Author manuscript; available in PMC 2013 December 27. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscriptwith an emphasis on machine structure and function, and the activities of effectors after translocation into the eukaryotic host. The T4S familyThis fascinatingly versatile translocation family can be classified into three subfamilies, each of which contributes in unique ways to pathogenesis ( Fig. 1; Table 1). The largest subfamily, the conjugation systems, are found in most species of Gram-negative and Grampositive bacteria. These systems mediate DNA transfer both within and between phylogenetically diverse species, and some systems even deliver DNA to fungi, plants and human cells 2,9-13 . Conjugation is an important contributor to genome plasticity, and therefore bacterial fitness under changing en...

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“…The icm/dot type IV secretion system is the major virulence system known in L. pneumophila; this system consists of 26 Icm/Dot proteins that probably constitute the secretion complex itself, as well as accessory proteins, such as chaperones (for a review, see reference 49). In the last 5 years, a growing number of protein substrates (RalF, LidA, Lep, Sid, Vip, Wip, Ylf, Leg, Vpd, Drr, and Ceg) that are translocated into host cells via the icm/dot secretion system were identified (for a review, see reference 42); in most cases the function of these proteins is not known, but two of them (SidF and SdhA) were shown to be required for inhibition of host cell death (5,27) and four others (RalF, LidA, DrrA/SidM, and SidJ) were shown to be required for manipulation of host cell vesicular trafficking (28,31,37,38), as well as other functions (11). Even though many icm/dot genes and many more icm/dot translocated substrates (IDTS), as well as potential IDTS, have been identified, there is only a limited amount of information about direct regulators that control the levels of expression of these genes.…”

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confidence: 99%

The Response Regulator CpxR Directly Regulates Expression of SeveralLegionella pneumophila icm/dotComponents as Well as New Translocated Substrates

2008

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Legionella pneumophila has been shown to utilize the icm/dot type IV secretion system for pathogenesis. This system was shown to be composed of icm/dot complex components and accessory proteins, as well as a large number of translocated substrates. Bioinformatic analysis of the regulatory regions of all the genes revealed that several icm/dot genes, as well as two genes encoding icm/dot translocated substrates, contain the conserved CpxR regulatory element, a regulator that has been shown previously to control the expression of the icmR gene. An experimental analysis, which included a comparison of gene expression in a L. pneumophila wild-type strain and gene expression in a cpxR deletion mutant, construction of mutants with mutations in the CpxR conserved regulatory elements, controlled expression studies, and mobility shift assays, demonstrated the direct relationship between the CpxR regulator and the expression of the genes. Furthermore, genomic analysis identified nine additional genes that contain a putative CpxR regulatory element; five of these genes (two legA genes and three ceg genes) were suggested previously to be putative icm/dot translocated substrates. The three ceg genes identified, which were shown previously to contain a putative PmrA regulatory element, were found here to be regulated by both CpxR and PmrA. The other six genes (two legA genes and four new genes products were found to be regulated by CpxR. Moreover, using the CyaA translocation assay, these nine gene products were found to be translocated into host cells in an Icm/Dot-dependent manner. Our results establish that the CpxR regulator is a fundamental regulator of the icm/dot type IV secretion system in L. pneumophila.

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A Bacterial Guanine Nucleotide Exchange Factor Activates ARF on Legionella Phagosomes

Cited by 525 publications

References 30 publications

Allosteric regulation of Arf GTPases and their GEFs at the membrane interface

Allosteric regulation of Arf GTPases and their GEFs at the membrane interface

The versatile bacterial type IV secretion systems

The Response Regulator CpxR Directly Regulates Expression of SeveralLegionella pneumophila icm/dotComponents as Well as New Translocated Substrates

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