Soluble NSF attachment protein receptor molecular mimicry by a<i>L</i><i>egionella pneumophila</i> Dot/Icm effector

King, Nathan P.; Newton, Patrice; Schuelein, Ralf; Brown, Darren L.; Petrů, Markéta; Žárský, Vojtěch; Doležal, Pavel; Luo, Lin; Bugarčić, Andrea; Stanley, Amanda C.; Murray, Rachael Z.; Collins, Brett M.; Teasdale, Rohan D.; Hartland, Elizabeth L.; Stow, Jennifer L.

doi:10.1111/cmi.12405

Cited by 26 publications

(27 citation statements)

References 73 publications

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“…6A). Next, to investigate a potential effect of the lspF mutation on the translocation function of the Dot/Icm system, we used a ␤-lactamase (Bla) reporter assay that has been used extensively to monitor L. pneumophila T4S within infected macrophages (74,75,109,110). To that end, plasmids expressing a fusion between AnkX, Lem3, LepB, LidA, SidD, or SidM and the Bla reporter were introduced into the WT and its lspF mutant, and after infection of BMD macrophages, we monitored the levels of Bla delivered into the host cell cytosol.…”

Section: Bmdm-ltmentioning

confidence: 99%

Type II Secretion Is Necessary for Optimal Association of the Legionella-Containing Vacuole with Macrophage Rab1B but Enhances Intracellular Replication Mainly by Rab1B-Independent Mechanisms

White

Cianciotto

2016

Infect Immun

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Previously, we documented that type II secretion (T2S) promotes intracellular infection of macrophages by Legionella pneumophila. In the present study, we identified infection events that are modulated by T2S by comparing the behaviors of wild-type and T2S mutant bacteria in murine bone marrow-derived macrophages and human U937 cells. Although the two strains behaved similarly for entry into the host cells and evasion of lysosomal fusion, the mutant was impaired in the ability to initiate replication between 4 and 8 h postentry and to grow to large numbers in the Legionella-containing vacuole (LCV), as evident at 12 h. At 4 h postinoculation, mutant LCVs had a significantly reduced association with Rab1B, a host GTPase that facilitates the tethering of endoplasmic reticulum (ER)-derived vesicles to LCVs. The mutant did not lose expression or translocation of six type IV secretion effectors (e.g., SidM) that are well known for mediating Rab1B association with the LCV, indicating that T2S promotes the interaction between the LCV and Rab1B via a novel mechanism. Interestingly, the mutant's growth defect was exacerbated in macrophages that had been depleted of Rab1B by short hairpin RNA (shRNA) treatment, indicating that T2S also potentiates events beyond Rab1B association. In support of this, a sidM lspF double mutant had an intracellular growth defect that was more dramatic than that of the lspF mutant (and a sidM mutant) and showed a growth difference of as much as a 400-fold compared to the wild type. Together, these data reveal a new role for T2S in intracellular infection that involves both Rab1B-dependent and Rab1B-independent processes. L egionella pneumophila is widespread in natural and man-made water systems and is best known as the etiologic agent of Legionnaires' disease (1-3). Recently, the incidence of pneumonias caused by Gram-negative L. pneumophila has roughly tripled in the United States and elsewhere (4-6). In water, L. pneumophila grows primarily as an intracellular parasite of amoebae (7-11). Human infection occurs mainly by the inhalation of contaminated water droplets originating from a wide range of aerosolgenerating devices (12,13). Yet the first case of person-to-person spread was reported in 2016 (14). In the lungs, L. pneumophila invades and grows in the resident macrophage population and ultimately triggers severe inflammation (3). In both amoebae and macrophages, the bacterium evades the host's degradative lysosomal pathway and replicates to large numbers within a membrane-bound vacuole, the Legionella-containing vacuole (LCV) (15, 16). The Dot/Icm type IV secretion (T4S) system of L. pneumophila plays a major role in pathogenesis (17-19). Indeed, the Dot/Icm apparatus translocates myriad proteins across the LCV membrane and into the host cell cytoplasm, and then the delivered effectors proceed to modulate a wide variety of host processes. One of the earliest and most notable events that has been ascribed to the Dot/Icm system is the recruitment of host GTPases and endoplasmic reticulu...

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Section: Bmdm-ltmentioning

confidence: 99%

Type II Secretion Is Necessary for Optimal Association of the Legionella-Containing Vacuole with Macrophage Rab1B but Enhances Intracellular Replication Mainly by Rab1B-Independent Mechanisms

White

Cianciotto

2016

Infect Immun

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“…Legionella pneumophila also expresses SNARE-like proteins. Legionella SNARE effector A (LseA) specifically interacts in vitro with multiple host SNAREs (41). Based on its subcellular localization, LseA is likely involved in mediating interactions between LCVs and Golgi-derived vesicles.…”

Section: Spacious Vacuoles Co-opt Host Membrane Fusion Machinerymentioning

confidence: 99%

Space: A Final Frontier for Vacuolar Pathogens

Case

Smith

Ficht

et al. 2016

Traffic

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There is a fundamental gap in our understanding of how a eukaryotic cell apportions the limited space within its cell membrane. Upon infection, a cell competes with intracellular pathogens for control of this same precious resource. The struggle between pathogen and host provides us with an opportunity to uncover the mechanisms regulating subcel-lural space by understanding how pathogens modulate vesicular traffic and membrane fusion events to create a specialized compartment for replication. By comparing several important intracellular pathogens, we review the molecular mechanism and trafficking pathways that drive two space allocation strategies, the formation of tight and spacious pathogen-containing vacuoles. Additionally, we discuss the potential advantages of each pathogenic lifestyle, the broader implications these lifestyles might have for cellular biology and outline exciting opportunities for future investigation.

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“…The Dot/Icm effectors SidM and LseA have been shown to modulate this secretory pathway by promoting the fusion of LCVs with ER-derived vesicles through effects on SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) complex formation (149, 150). SNARES are responsible for the docking and fusion of many different vesicle-mediated transport events.…”

Section: T4ss Effectors and Their Roles In Pathogenesismentioning

confidence: 99%

Mechanism and Function of Type IV Secretion During Infection of the Human Host

2016

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Bacterial pathogens employ type IV secretion systems (T4SSs) for various purposes to aid in survival and proliferation in eukaryotic host. One large T4SS subfamily, the conjugation systems, confers a selective advantage to the invading pathogen in clinical settings through dissemination of antibiotic resistance genes and virulence traits. Besides their intrinsic importance as principle contributors to the emergence of multiply drug-resistant ‘superbugs’, detailed studies of these highly tractable systems have generated important new insights into the mode of action and architectures of paradigmatic T4SSs as a foundation for future efforts aimed at suppressing T4SS machine function. Over the past decade, extensive work on the second large T4SS subfamily, the effector translocators, has identified a myriad of mechanisms employed by pathogens to subvert, subdue, or bypass cellular processes and signaling pathways of the host cell. An overarching theme in the evolution of many effectors is that of molecular mimicry. These effectors carry domains similar to those of eukaryotic proteins and exert their effects through stealthy interdigitation of cellular pathways, often with the outcome not of inducing irreversible cell damage but rather of reversibly modulating cellular functions. This chapter summarizes the major developments for the actively studied pathogens with an emphasis on the structural and functional diversity of the T4SSs and the emerging common themes surrounding effector function in the human host.

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Soluble NSF attachment protein receptor molecular mimicry by aLegionella pneumophila Dot/Icm effector

Cited by 26 publications

References 73 publications

Type II Secretion Is Necessary for Optimal Association of the Legionella-Containing Vacuole with Macrophage Rab1B but Enhances Intracellular Replication Mainly by Rab1B-Independent Mechanisms

Type II Secretion Is Necessary for Optimal Association of the Legionella-Containing Vacuole with Macrophage Rab1B but Enhances Intracellular Replication Mainly by Rab1B-Independent Mechanisms

Space: A Final Frontier for Vacuolar Pathogens

Mechanism and Function of Type IV Secretion During Infection of the Human Host

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