Exploitation of conserved eukaryotic host cell farnesylation machinery by an F-box effector of <i>Legionella pneumophila</i>

Price, Christopher; Al-Quadan, Tasneem; Šantić, Marina; Jones, Snake; Kwaik, Yousef Abu

doi:10.1084/jem.20100771

Cited by 126 publications

(239 citation statements)

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“…Yet another F-boxcontaining Ank is L. pneumophila AnkX, which exploits SKP1 to mediate ubiquitination and subsequent proteosomal degradation of unknown host cell protein substrates to ultimately yield free amino acids that are essential for the bacterium's intracellular growth (79,80). AnkX exploits another eukaryotic process, farnesylation, to mediate its association with the Legionella-containing vacuole (81). Finally, Coxiella burnetii AnkG binds both host p32 and importin-␣1 in order to traffic into the nucleus and inhibit apoptosis (82,83).…”

Section: Discussionmentioning

confidence: 99%

Orientia tsutsugamushi Modulates Endoplasmic Reticulum-Associated Degradation To Benefit Its Growth

et al. 2018

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Orientia tsutsugamushi, an obligate intracellular bacterium that is auxotrophic for the aromatic amino acids and histidine, causes scrub typhus, a potentially deadly infection that threatens 1 billion people. O. tsutsugamushi growth is minimal during the first 24 to 48 h of infection but its growth becomes logarithmic thereafter. How the pathogen modulates cellular functions to support its growth is poorly understood. The unfolded protein response (UPR) is a cytoprotective pathway that relieves endoplasmic reticulum (ER) stress by promoting ER-associated degradation (ERAD) of misfolded proteins. Here, we show that O. tsutsugamushi invokes the UPR in the first 48 h and benefits from ER stress in an amino acid-dependent manner. O. tsutsugamushi also impedes ERAD during this time period. By 72 h, ER stress is alleviated and ERAD proceeds unhindered. Sustained inhibition of ERAD using RNA interference results in an O. tsutsugamushi growth defect at 72 h that can be rescued by amino acid supplementation. Thus, O. tsutsugamushi temporally stalls ERAD until ERAD-derived amino acids are needed to support its growth. The O. tsutsugamushi effector Ank4 is linked to this phenomenon. Ank4 interacts with Bat3, a eukaryotic chaperone that is essential for ERAD, and is transiently expressed by O. tsutsugamushi during the infection period when it inhibits ERAD. Ectopically expressed Ank4 blocks ERAD to phenocopy O. tsutsugamushi infection. Our data reveal a novel mechanism by which an obligate intracellular bacterial pathogen modulates ERAD to satisfy its nutritional virulence requirements.

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Section: Discussionmentioning

confidence: 99%

Orientia tsutsugamushi Modulates Endoplasmic Reticulum-Associated Degradation To Benefit Its Growth

et al. 2018

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“…Here, we report that LpdA is an L. pneumophila effector that exploits host cell mediated posttranslational S-palmitoylation as membrane-targeting mechanism. To our knowledge, LpdA is the first palmitolylated L. pneumophila effector, although other T4SS effectors have previously been shown to exploit posttranslational prenylation for membrane targeting (19,20). Bacterial type III secretion system effectors, such as Salmonella SspH2 and SseI or Pseudomonas AvrPphB, as well as several viruses, have been shown to use posttranslational palmitoylation for subcellular targeting (54)(55)(56), suggesting that its exploitation is an ancient strategy in the coevolution of pathogens and hosts.…”

Section: Discussionmentioning

confidence: 99%

“…Together, these irreversible modifications increase the hydrophobicity and membrane affinity of the effectors, facilitating their membrane association. Legionella ensures the efficient modification of effectors by recruiting host proteins, such as farnesyl transferase, RCE-1, and IcmT to the LCV in a T4SS-dependent manner (20).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%

“…To achieve membrane association, Legionella effectors highjack at least two common host cell mechanisms. Several effectors contain a classical C-terminal CAAX-box motif which is recognized by prenyltransferases and posttranslationally modified with a geranylgeranyl (20-carbon) or a farnesyl (15-carbon) lipid anchor (19,20). After the lipid transfer, Ras-converting enzyme 1 (RCE-1) removes the amino acid residues after the modified cysteine and isoprenyl cysteine carboxyl methyltransferase (IcmT) methylates the new C terminus.…”

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confidence: 99%

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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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Host Lipidation: A Mechanism for Spatial Regulation of Legionella Effectors

Ivanov¹,

Roy²

2013

Current Topics in Microbiology and Immunology

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Bacterial pathogens have evolved the capacity to translocate proteins into the cytosol of infected cells to manipulate host processes. How do pathogens regulate spatially these bacterial effector proteins once they are released into the host cell? One mechanism, which is used by Legionella and other bacterial pathogens, is to encode effectors that mimic the substrates of eukaryotic lipid transferases. In this review we discuss three membrane-targeting pathways in eukaryotes that are exploited by Legionella and other pathogens-prenylation, palmitoylation, and myristoylation. Lipidation of bacterial substrates primes the effectors for coincidence detection-mediated targeting onto membrane-bound organelles by increasing membrane affinity. Intracellular membrane-targeting strategies that exploit protein fatty acylation and prenylation direct bacterial effectors to compartments where their target substrates reside and thus are critical for effector function.

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Exploitation of conserved eukaryotic host cell farnesylation machinery by an F-box effector of Legionella pneumophila

Cited by 126 publications

References 40 publications

Orientia tsutsugamushi Modulates Endoplasmic Reticulum-Associated Degradation To Benefit Its Growth

Orientia tsutsugamushi Modulates Endoplasmic Reticulum-Associated Degradation To Benefit Its Growth

Legionella pneumophila Effector LpdA Is a Palmitoylated Phospholipase D Virulence Factor

Host Lipidation: A Mechanism for Spatial Regulation of Legionella Effectors

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