Protein Kinase LegK2 Is a Type IV Secretion System Effector Involved in Endoplasmic Reticulum Recruitment and Intracellular Replication of Legionella pneumophila

Hervet, Éva; Charpentier, Xavier; Vianney, Anne; Lazzaroni, Jean-Claude; Gilbert, Christophe; Atlan, Danièle; Doublet, Patricia

doi:10.1128/iai.00805-10

Cited by 81 publications

(98 citation statements)

References 76 publications

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“…The ER is one of the organelles of the host cell that is targeted by intracellular pathogens. Certain bacterial toxins also hijack the ER for entry and intracellular survival (35). In addition, in the Ras/Raf/MEK/ERK signaling cascade, several mediators within this pathway are exquisitely regulated by subcellular compartmentalization (44,45).…”

Section: Discussionmentioning

confidence: 99%

“…Several effector proteins from pathogenic bacteria were shown to mimick host proteins such as phosphatases or kinases to evade host immune defenses (33,35,(49)(50)(51). Because Mce3E has a DEF motif and could interact with ERK1/2 directly, we initially examined whether Mce3E could be able to dephosphorylate p-ERK directly, but we were not able to demonstrate the phosphatase activity of Mce3E toward p-ERK in vitro.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, we proposed that Mce3E interacts with ERK1/2, but not MEK1. Several effectors from pathogenic bacteria such as Legionella effectors display distinctive eukaryotic domains, among which are protein kinase or phosphatase domains (33)(34)(35). In our efforts to search for the functional domains/ motifs within Mce3E, we identified a potential DEF motif, an ERKdocking motif that possesses a consensus sequence of FXFP, in Mce3E (FPFP) using in silico analysis (http://scansite.mit.edu/) (36).…”

Section: Mce3e Interacts With Erk In a Def-dependent Mannermentioning

confidence: 99%

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Mycobacterium tuberculosis Mce3E Suppresses Host Innate Immune Responses by Targeting ERK1/2 Signaling

Chai

Zhang

et al. 2015

The Journal of Immunology

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Crucial to the pathogenesis of the tuberculosis (TB)-causing pathogen Mycobacterium tuberculosis is its ability to subvert host immune defenses to promote its intracellular survival. The mammalian cell entry protein 3E (Mce3E), located in the region of difference 15 of the M. tuberculosis genome and absent in Mycobacterium bovis bacillus Calmette-Guérin, has an essential role in facilitating the internalization of mammalian cells by mycobacteria. However, relatively little is known about the role of Mce3E in modulation of host innate immune responses. In this study, we demonstrate that Mce3E inhibits the activation of the ERK1/2 signaling pathway, leading to the suppression of Tnf and Il6 expression, and the promotion of mycobacterial survival within macrophages. Mce3E interacts and colocalizes with ERK1/2 at the endoplasmic reticulum in a DEF motif (an ERK-docking motif)–dependent manner, relocates ERK1/2 from cytoplasm to the endoplasmic reticulum, and finally reduces the association of ERK1/2 with MEK1 and blocks the nuclear translocation of phospho-ERK1/2. A DEF motif mutant form of Mce3E (F294A) loses its ability to suppress Tnf and Il6 expression and to promote intracellular survival of mycobacteria. Inhibition of the ERK1/2 pathway in macrophages using U0126, a specific inhibitor of the ERK pathway, also leads to the suppressed Tnf and Il6 expression and the enhanced intracellular survival of mycobacteria. Taken together, these results suggest that M. tuberculosis Mce3E exploits the ERK1/2 signaling pathway to suppress host innate immune responses, providing a potential Mce3E–ERK1/2 interface–based drug target against M. tuberculosis.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Mce3e Interacts With Erk In a Def-dependent Mannermentioning

confidence: 99%

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Mycobacterium tuberculosis Mce3E Suppresses Host Innate Immune Responses by Targeting ERK1/2 Signaling

Chai

Zhang

et al. 2015

The Journal of Immunology

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“…Two additional candidate effectors, LegK2 and SidJ, which seem to be involved in orchestrating alternative ER recruitment mechanisms, have been identified on the basis of reduced or delayed ER accumulation on the LCV of L. pneumophila effector null mutants (Liu and Luo 2007;Hervet et al 2011). The underlying molecular mechanisms are poorly defined.…”

Section: Additional Effectors With Important Roles In Lcv Maturationmentioning

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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“…Monitoring of L. pneumophila intracellular growth in D. discoideum was adapted from an assay described previously (Hervet et al, 2011). L. pneumophila bacteria harboring a plasmid expressing mCherry were grown on BYE liquid medium containing 2 mM IPTG and chloramphenicol for 4 days at 30˚C.…”

Section: Intracellular Replicationmentioning

confidence: 99%

Defective lysosome maturation and Legionella pneumophila replication in Dictyostelium ArfGAP ACAP-A mutant cells

Baïlo

Cosson²,

Charette

et al. 2014

Journal of Cell Science

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Dictyostelium discoideum ACAP-A is an Arf GTPase-activating protein (GAP) involved in cytokinesis, cell migration and actin cytoskeleton dynamics. In mammalian cells, ACAP family members regulate endocytic protein trafficking. Here, we explored the function of ACAP-A in the endocytic pathway of D. discoideum. In the absence of ACAP-A, the efficiency of fusion between postlysosomes and the plasma membrane was reduced, resulting in the accumulation of post-lysosomes. Moreover, internalized fluidphase markers showed extended intracellular transit times, and the transfer kinetics of phagocyted particles from lysosomes to postlysosomes was reduced. Neutralization of lysosomal pH, one essential step in lysosome maturation, was also delayed. Whereas expression of ACAP-A-GFP in acapA 2 cells restored normal particle transport kinetics, a mutant ACAP-A protein with no GAP activity towards the small GTPase ArfA failed to complement this defect. Taken together, these data support a role for ACAP-A in maturation of lysosomes into post-lysosomes through an ArfAdependent mechanism. In addition, we reveal that ACAP-A is required for efficient intracellular growth of Legionella pneumophila, a pathogen known to subvert the endocytic host cell machinery for replication. This further emphasizes the role of ACAP-A in the endocytic pathway.

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Protein Kinase LegK2 Is a Type IV Secretion System Effector Involved in Endoplasmic Reticulum Recruitment and Intracellular Replication of Legionella pneumophila

Cited by 81 publications

References 76 publications

Mycobacterium tuberculosis Mce3E Suppresses Host Innate Immune Responses by Targeting ERK1/2 Signaling

Mycobacterium tuberculosis Mce3E Suppresses Host Innate Immune Responses by Targeting ERK1/2 Signaling

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

Defective lysosome maturation and Legionella pneumophila replication in Dictyostelium ArfGAP ACAP-A mutant cells

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