LtpD Is a Novel Legionella pneumophila Effector That Binds Phosphatidylinositol 3-Phosphate and Inositol Monophosphatase IMPA1

Harding, Clare R.; Mattheis, Corinna; Mousnier, Aurélie; Oates, Clare V.; Hartland, Elizabeth L.; Frankel, Gad; Schroeder, Gunnar N.

doi:10.1128/iai.01054-13

Cited by 30 publications

(23 citation statements)

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“…Legionella-containing vacuoles acquire PtdIns(3)P within 1 min after uptake and gradually lose the PI lipid within a 2 h time period (Weber et al, 2014a). Several Icm/Dot substrates (LidA, LptD, RidL and SetA) bind PtdIns(3)P in vitro, and therefore, might employ this PI as an LCV membrane anchor (Brombacher et al, 2009;Hilbi et al, 2011b;Jank et al, 2012;Finsel et al, 2013;Harding et al, 2013;Fig. 1).…”

Section: Interference With Cell Uptake and Endocytosismentioning

confidence: 99%

“…Activator of phosphatidic acid phosphatase Pah1 Zhu et al, 2011;Viner et al, 2012 LegC2 ( et al, 2003;Derre and Isberg, 2005;Brombacher et al, 2009;Schoebel et al, 2011;Cheng et al, 2012;Neunuebel et al, 2012 NF-κB activation ND Losick et al, 2010 Manipulation of mitochondrial metabolite membrane transport Mitochondrial carrier family transporter (ATP) Dolezal et al, 2012 LpdA ( Kubori et al, 2008;2010 LseA (Lpc2110) Subversion of vesicle trafficking SNARE mimic King et al, 2014 LtpD (Lpw3701) Modulation of PI metabolism Binds to (myo)-1-monophosphatase 1 (IMPA1) and PtdIns(3)P Harding et al, 2013 PieA (Lpg1963) Alteration of lysosome morphology ND Ninio et al, 2009 Modulation of Rab activity Binds Rab1, -5, -6, -7, -10 Ninio et al, 2009;Mousnier et al, 2014 be removed from the LCV by the effector SidP (Toulabi et al, 2013). SidP is a PI 3-phosphatase containing the 'CX5R' motif that hydrolyzes in vitro PtdIns(3)P as well as PtdIns(3,5)P2, thus possibly contributing to the evasion of the endocytic pathway by LCVs.…”

Section: Interference With Cell Uptake and Endocytosismentioning

confidence: 99%

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Formation of a pathogen vacuole according toLegionella pneumophila: how to kill one bird with many stones

2015

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SummaryLegionella species are ubiquitous, waterborne bacteria that thrive in numerous ecological niches. Yet, in contrast to many other environmental bacteria, Legionella spp. are also able to grow intracellularly in predatory protozoa. This feature mainly accounts for the pathogenicity of Legionella pneumophila, which causes the majority of clinical cases of a severe pneumonia termed Legionnaires' disease. The pathomechanism underlying L. pneumophila infection is based on macrophage resistance, which in turn is largely defined by the opportunistic pathogen's resistance towards amoebae. L. pneumophila replicates in macrophages or amoebae in a unique membranebound compartment, the Legionella-containing vacuole (LCV). LCV formation requires the bacterial intracellular multiplication/defective for organelle trafficking (Icm/Dot) type IV secretion system and involves a plethora of translocated effector proteins, which subvert pivotal processes in the host cell. Of the ca. 300 different experimentally validated Icm/Dot substrates, about 50 have been studied and attributed a cellular function to date. The versatility and ingenuity of these effectors' mode of actions is striking. In this review, we summarize insight into the cellular functions and biochemical activities of well-characterized L. pneumophila effector proteins and the host pathways they target. Recent studies not only substantially increased our knowledge about pathogen-host interactions, but also shed light on novel biological mechanisms.

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Section: Interference With Cell Uptake and Endocytosismentioning

confidence: 99%

Section: Interference With Cell Uptake and Endocytosismentioning

confidence: 99%

Formation of a pathogen vacuole according toLegionella pneumophila: how to kill one bird with many stones

2015

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“…Preferences in the PIP-binding specificity might thereby indicate the subcellular compartments to which these effectors are targeted or the stage of infection at which they are associated with the LCV. PI(3)P is preferentially bound by LtpD (Harding et al 2013a), RidL (Finsel et al 2013), SetA (Jank et al 2012), LidA (Brombacher et al 2009), and LpnE ). The effectors SidC, Lem4, Lem28, and SidM/DrrA specifically bind PI(4)P (Ragaz et al 2008;Brombacher et al 2009;Hubber et al 2014).…”

Section: Adjusting the Lcv Lipid Composition To Resemble The Golgimentioning

confidence: 99%

“…In concert, these effectors could catalyze the breakdown of phospholipids to phosphatidic acid and further to diacylglycerol (Viner et al 2012). The effector LtpD was shown to bind the host cell enzyme inositol(myo)-1(or 4)-monophosphatase 1 (IMPA1), which dephosphorylates inositol monophosphate to generate free inositol, a limiting step in the biosynthesis of PIs (Harding et al 2013a). LpdA, LecE, and LtpD localize to the LCV; however, the impact of their action on the lipid composition of the LCV and on the interaction with endosomal and other vesicular trafficking pathways of the host cell still remains to be determined.…”

Section: Adjusting the Lcv Lipid Composition To Resemble The Golgimentioning

confidence: 99%

Creating a customized intracellular niche: subversion of host cell signaling byLegionellatype IV secretion system effectors

Mattheis

Tate

et al. 2015

Can. J. Microbiol.

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Abstract:The Gram-negative facultative intracellular pathogen Legionella pneumophila infects a wide range of different protozoa in the environment and also human alveolar macrophages upon inhalation of contaminated aerosols. Inside its hosts, it creates a defined and unique compartment, termed the Legionella-containing vacuole (LCV), for survival and replication. To establish the LCV, L. pneumophila uses its Dot/Icm type IV secretion system (T4SS) to translocate more than 300 effector proteins into the host cell. Although it has become apparent in the past years that these effectors subvert a multitude of cellular processes and allow Legionella to take control of host cell vesicle trafficking, transcription, and translation, the exact function of the vast majority of effectors still remains unknown. This is partly due to high functional redundancy among the effectors, which renders conventional genetic approaches to elucidate their role ineffective. Here, we review the current knowledge about Legionella T4SS effectors, highlight open questions, and discuss new methods that promise to facilitate the characterization of T4SS effector functions in the future.Key words: Legionella, type IV secretion system, effectors, Legionella-containing vacuole.Résumé : Le pathogène intracellulaire facultatif à Gram négatif Legionella pneumophila infecte une large gamme de différents protozoaires environnementaux de même que les macrophages alvéolaires humains des suites de l'inhalation d'aérosols contaminés. À l'intérieur de ses hôtes, il crée un compartiment précis et unique nommé vacuole contenant Legionella (« Legionella-containing vacuole », LCV) pour sa survie et sa multiplication. Afin d'établir une LCV, L. pneumophila utilise sont système de sécrétion de type IV (SST4) Dot/Icm, rendant possible la translocation de plus de 300 protéines effectrices dans la cellule hôte. Au cours des dernières années, on a établi que ces effecteurs subvertissent une multitude de processus cellulaires et permettent à Legionella de prendre le contrôle du trafic cellulaire, de la transcription et de la traduction. Or, la fonction exacte de la grande majorité des effecteurs est toujours inconnue. L'importante redondance fonctionnelle au sein des effecteurs explique en partie cette incertitude et invalide les approches génétiques conventionnelles adoptées pour élucider leur rôle. Dans le présent ouvrage, nous passons en revue les connaissances actuelles entourant les effecteurs SST4 de Legionella, faisons ressortir certaines interrogations, et abordons de nouvelles méthodes qui promettent de faciliter la caractérisation de la fonction des effecteurs SST4. [Traduit par la Rédaction] Mots-clés : Legionella, système de sécrétion de type IV, effecteurs, vacuole contenant Legionella.

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“…Alternatively to using a covalently attached lipid anchor, several Legionella effectors associate with membranes by binding phosphatidylinositol phosphates (PIPs) (16,21), negatively charged glycerophospholipids which contain a mono-or polyphosphorylated myo-inositol ring (22). PIPs are versatile signaling molecules, and specific enrichment of one subspecies gives identity to organelle membranes, leading to selective recruitment of PIP-binding proteins.…”

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confidence: 99%

Legionella pneumophila Effector LpdA Is a Palmitoylated Phospholipase D Virulence Factor

et al. 2015

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dLegionella pneumophila is a bacterial pathogen that thrives in alveolar macrophages, causing a severe pneumonia. The virulence of L. pneumophila depends on its Dot/Icm type IV secretion system (T4SS), which delivers more than 300 effector proteins into the host, where they rewire cellular signaling to establish a replication-permissive niche, the Legionella-containing vacuole (LCV). Biogenesis of the LCV requires substantial redirection of vesicle trafficking and remodeling of intracellular membranes. In order to achieve this, several T4SS effectors target regulators of membrane trafficking, while others resemble lipases. Here, we characterized LpdA, a phospholipase D effector, which was previously proposed to modulate the lipid composition of the LCV. We found that ectopically expressed LpdA was targeted to the plasma membrane and Rab4-and Rab14-containing vesicles. Subcellular targeting of LpdA required a C-terminal motif, which is posttranslationally modified by S-palmitoylation. Substrate specificity assays showed that LpdA hydrolyzed phosphatidylinositol, -inositol-3-and -4-phosphate, and phosphatidylglycerol to phosphatidic acid (PA) in vitro. In HeLa cells, LpdA generated PA at vesicles and the plasma membrane. Imaging of different phosphatidylinositol phosphate (PIP) and organelle markers revealed that while LpdA did not impact on membrane association of various PIP probes, it triggered fragmentation of the Golgi apparatus. Importantly, although LpdA is translocated inefficiently into cultured cells, an L. pneumophila ⌬lpdA mutant displayed reduced replication in murine lungs, suggesting that it is a virulence factor contributing to L. pneumophila infection in vivo.L egionella pneumophila is a bacterial pathogen which infects and replicates in protozoa, as well as in human alveolar macrophages and lung epithelial cells, causing a severe pneumonia called Legionnaires' disease (1). Several secretion systems allow L. pneumophila to export proteins into its environment and interact with host cells (1, 2). The Legionella type I and type II secretion systems (T1SS and T2SS) have been shown to contribute to L. pneumophila virulence (3, 4); however, only the Dot/Icm type IV secretion system (T4SS) is essential for intracellular replication and pathogenesis (5, 6). The Dot/Icm T4SS delivers more than 300 effector proteins into the host cell, where they manipulate cell signaling (7,8). This enables the bacteria to evade phagolysosomal degradation and instead establish a replication-permissive endoplasmic reticulum (ER)-derived niche, the Legionella-containing vacuole (LCV) (9-11).The biogenesis of the LCV is a multistep process and involves substantial remodeling of the membrane of the nascent Legionella phagosome (12, 13). Consequently, a large number of effectors secreted by Legionella are membrane-associated proteins which target cellular regulators of membrane trafficking, such as Rab GTPases (14, 15), or directly exploit and manipulate host lipids (16-18). To achieve membrane association, Legionella effector...

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LtpD Is a Novel Legionella pneumophila Effector That Binds Phosphatidylinositol 3-Phosphate and Inositol Monophosphatase IMPA1

Cited by 30 publications

References 43 publications

Formation of a pathogen vacuole according toLegionella pneumophila: how to kill one bird with many stones

Formation of a pathogen vacuole according toLegionella pneumophila: how to kill one bird with many stones

Creating a customized intracellular niche: subversion of host cell signaling byLegionellatype IV secretion system effectors

Legionella pneumophila Effector LpdA Is a Palmitoylated Phospholipase D Virulence Factor

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