Arginine glycosylation enhances methylglyoxal detoxification

AbstractType III secretion system effector proteins have primarily been characterized for their interactions with host cell proteins and their ability to disrupt host signaling pathways. We are testing the hypothesis that some effectors are active within the bacterium, where they modulate bacterial signal transduction and physiology. We previously determined that the Citrobacter rodentium effector NleB possesses an intra-bacterial glycosyltransferase activity that increases glutathione synthetase activity to protect the bacterium from oxidative stress. Here we investigated the potential intra-bacterial activities of NleB orthologs in Salmonella enterica and found that SseK1 and SseK3 mediate resistance to methylglyoxal. SseK1 glycosylates specific arginine residues on four proteins involved in methylglyoxal detoxification, namely GloA (R9), GloB (R190), GloC (R160), and YajL (R149). SseK1-mediated Arg-glycosylation of these four proteins significantly enhances their catalytic activity, thus providing another important example of the intra-bacterial activities of type three secretion system effector proteins. These data are also the first demonstration that a Salmonella T3SS effector is active within the bacterium.

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Regulation of the Locus of Enterocyte Effacement in Attaching and Effacing Pathogens

Journal of Bacteriology ◽

10.1128/jb.00336-17 ◽

2017 ◽

Vol 200 (2) ◽

Cited By ~ 14

Author(s):

R. Christopher D. Furniss ◽

Abigail Clements

Keyword(s):

Secretion System ◽

Effector Proteins ◽

The Core ◽

Genetic Feature ◽

Gut Epithelium ◽

Type Three Secretion System ◽

Gut Mucosa ◽

Enterocyte Effacement ◽

Type Three Secretion ◽

Complex Regulatory Network

ABSTRACTAttaching and effacing (AE) pathogens colonize the gut mucosa using a type three secretion system (T3SS) and a suite of effector proteins. The locus of enterocyte effacement (LEE) is the defining genetic feature of the AE pathogens, encoding the T3SS and the core effector proteins necessary for pathogenesis. Extensive research has revealed a complex regulatory network that senses and responds to a myriad of host- and microbiota-derived signals in the infected gut to control transcription of the LEE. These signals include microbiota-liberated sugars and metabolites in the gut lumen, molecular oxygen at the gut epithelium, and host hormones. Recent research has revealed that AE pathogens also recognize physical signals, such as attachment to the epithelium, and that the act of effector translocation remodels gene expression in infecting bacteria. In this review, we summarize our knowledge to date and present an integrated view of how chemical, geographical, and physical cues regulate the virulence program of AE pathogens during infection.

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Chemical Inhibitors of the Type Three Secretion System: Disarming Bacterial Pathogens

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00975-12 ◽

2012 ◽

Vol 56 (11) ◽

pp. 5433-5441 ◽

Cited By ~ 69

Author(s):

Miles C. Duncan ◽

Roger G. Linington ◽

Victoria Auerbuch

Keyword(s):

Bacterial Infections ◽

Pathogenic Bacteria ◽

Bacterial Pathogens ◽

Secretion System ◽

Effector Proteins ◽

Host Cells ◽

Magic Bullet ◽

Antimicrobial Drugs ◽

Type Three Secretion System ◽

Type Three Secretion

ABSTRACTThe recent and dramatic rise of antibiotic resistance among bacterial pathogens underlies the fear that standard treatments for infectious disease will soon be largely ineffective. Resistance has evolved against nearly every clinically used antibiotic, and in the near future, we may be hard-pressed to treat bacterial infections previously conquered by “magic bullet” drugs. While traditional antibiotics kill or slow bacterial growth, an important emerging strategy to combat pathogens seeks to block the ability of bacteria to harm the host by inhibiting bacterial virulence factors. One such virulence factor, the type three secretion system (T3SS), is found in over two dozen Gram-negative pathogens and functions by injecting effector proteins directly into the cytosol of host cells. Without T3SSs, many pathogenic bacteria are unable to cause disease, making the T3SS an attractive target for novel antimicrobial drugs. Interdisciplinary efforts between chemists and microbiologists have yielded several T3SS inhibitors, including the relatively well-studied salicylidene acylhydrazides. This review highlights the discovery and characterization of T3SS inhibitors in the primary literature over the past 10 years and discusses the future of these drugs as both research tools and a new class of therapeutic agents.

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Extra! Extracellular Effector Delivery into Host Cells via the Type 3 Secretion System

mBio ◽

10.1128/mbio.00594-17 ◽

2017 ◽

Vol 8 (3) ◽

Cited By ~ 2

Author(s):

Melissa M. Kendall

Keyword(s):

Host Cell ◽

Secretion System ◽

Effector Proteins ◽

Host Cells ◽

Alternative Mechanism ◽

Host Cell Membrane ◽

Type Three Secretion System ◽

Host Signaling ◽

Type 3 Secretion System ◽

Type 3

ABSTRACT The type three secretion system (T3SS) is critical for the virulence of diverse bacterial pathogens. Pathogens use the T3SS to deliver effector proteins into host cells and manipulate host signaling pathways. The prevailing mechanism is that effectors translocate from inside the T3SS directly into the host cell. Recent studies reveal an alternative mechanism of effector translocation, in which an effector protein located outside the bacterial cell relies on the T3SS for delivery into host cells. Tejeda-Dominguez et al. (F. Tejeda-Dominguez, J. Huerta-Cantillo, L. Chavez-Dueñas, and F. Navarro-Garcia, mBio 8:e00184-17, 2017, https://doi.org/10.1128/mBio.00184-17 !) demonstrate that the EspC effector of enteropathogenic Escherichia coli is translocated by binding to the outside of the T3SS and subsequently gains access to the host cell cytoplasm through the T3SS pore embedded within the host cell membrane. This work reveals a novel mechanism of translocation that is likely relevant for a variety of other pathogens that use the T3SS as part of their virulence arsenal.

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Salmonella Pathogenicity Island 1 (SPI-1): The Evolution and Stabilization of a Core Genomic Type Three Secretion System

Microorganisms ◽

10.3390/microorganisms8040576 ◽

2020 ◽

Vol 8 (4) ◽

pp. 576

Author(s):

Nicole A. Lerminiaux ◽

Keith D. MacKenzie ◽

Andrew D. S. Cameron

Keyword(s):

Transcription Factors ◽

Pathogenicity Island ◽

Secretion System ◽

Effector Proteins ◽

Gene Promoters ◽

Salmonella Pathogenicity Island ◽

Evolutionary Origins ◽

Type Three Secretion System ◽

History Of ◽

Type Three Secretion

Salmonella Pathogenicity Island 1 (SPI-1) encodes a type three secretion system (T3SS), effector proteins, and associated transcription factors that together enable invasion of epithelial cells in animal intestines. The horizontal acquisition of SPI-1 by the common ancestor of all Salmonella is considered a prime example of how gene islands potentiate the emergence of new pathogens with expanded niche ranges. However, the evolutionary history of SPI-1 has attracted little attention. Here, we apply phylogenetic comparisons across the family Enterobacteriaceae to examine the history of SPI-1, improving the resolution of its boundaries and unique architecture by identifying its composite gene modules. SPI-1 is located between the core genes fhlA and mutS, a hotspot for the gain and loss of horizontally acquired genes. Despite the plasticity of this locus, SPI-1 demonstrates stable residency of many tens of millions of years in a host genome, unlike short-lived homologous T3SS and effector islands including Escherichia ETT2, Yersinia YSA, Pantoea PSI-2, Sodalis SSR2, and Chromobacterium CPI-1. SPI-1 employs a unique series of regulatory switches, starting with the dedicated transcription factors HilC and HilD, and flowing through the central SPI-1 regulator HilA. HilA is shared with other T3SS, but HilC and HilD may have their evolutionary origins in Salmonella. The hilA, hilC, and hilD gene promoters are the most AT-rich DNA in SPI-1, placing them under tight control by the transcriptional repressor H-NS. In all Salmonella lineages, these three promoters resist amelioration towards the genomic average, ensuring strong repression by H-NS. Hence, early development of a robust and well-integrated regulatory network may explain the evolutionary stability of SPI-1 compared to T3SS gene islands in other species.

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Cinnamaldehyde inhibits type three secretion system in Salmonella enterica serovar Typhimurium by affecting the expression of key effector proteins

Veterinary Microbiology ◽

10.1016/j.vetmic.2019.108463 ◽

2019 ◽

Vol 239 ◽

pp. 108463 ◽

Cited By ~ 3

Author(s):

Yan Liu ◽

Yong Zhang ◽

Yonglin Zhou ◽

Tingting Wang ◽

Xuming Deng ◽

...

Keyword(s):

Salmonella Enterica ◽

Salmonella Enterica Serovar Typhimurium ◽

Secretion System ◽

Effector Proteins ◽

Type Three Secretion System ◽

Serovar Typhimurium ◽

Type Three Secretion

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The Impact of ExoS onPseudomonas aeruginosaInternalization by Epithelial Cells Is Independent offleQand Correlates with Bistability of Type Three Secretion System Gene Expression

mBio ◽

10.1128/mbio.00668-18 ◽

2018 ◽

Vol 9 (3) ◽

Cited By ~ 8

Author(s):

Abby R. Kroken ◽

Camille K. Chen ◽

David J. Evans ◽

Timothy L. Yahr ◽

Suzanne M. J. Fleiszig

Keyword(s):

Epithelial Cells ◽

Intracellular Survival ◽

Secretion System ◽

Host Cells ◽

Content Type ◽

T3ss Effector ◽

Type Three Secretion System ◽

The Impact ◽

Type Three Secretion

ABSTRACTPseudomonas aeruginosais internalized into multiple types of epithelial cellin vitroandin vivoand yet is often regarded as an exclusively extracellular pathogen. Paradoxically, ExoS, a type three secretion system (T3SS) effector, has antiphagocytic activities but is required for intracellular survival ofP. aeruginosaand its occupation of bleb niches in epithelial cells. Here, we addressed mechanisms for this dichotomy using invasive (ExoS-expressing)P. aeruginosaand corresponding effector-null isogenic T3SS mutants, effector-null mutants of cytotoxicP. aeruginosawith and without ExoS transformation, antibiotic exclusion assays, and imaging using a T3SS-GFP reporter. Except for effector-null PA103, all strains were internalized while encoding ExoS. Intracellular bacteria showed T3SS activation that continued in replicating daughter cells. Correcting thefleQmutation in effector-null PA103 promoted internalization by >10-fold with or without ExoS. Conversely, mutatingfleQin PAO1 reduced internalization by >10-fold, also with or without ExoS. Effector-null PA103 remained less well internalized than PAO1 matched forfleQstatus, but only with ExoS expression, suggesting additional differences between these strains. Quantifying T3SS activation using GFP fluorescence and quantitative reverse transcription-PCR (qRT-PCR) showed that T3SS expression was hyperinducible for strain PA103ΔexoUTversus other isolates and was unrelated tofleQstatus. These findings support the principle thatP. aeruginosais not exclusively an extracellular pathogen, with internalization influenced by the relative proportions of T3SS-positive and T3SS-negative bacteria in the population during host cell interaction. These data also challenge current thinking about T3SS effector delivery into host cells and suggest that T3SS bistability is an important consideration in studyingP. aeruginosapathogenesis.IMPORTANCEP. aeruginosais often referred to as an extracellular pathogen, despite its demonstrated capacity to invade and survive within host cells. Fueling the confusion,P. aeruginosaencodes T3SS effectors with anti-internalization activity that, paradoxically, play critical roles in intracellular survival. Here, we sought to address why ExoS does not prevent internalization of theP. aeruginosastrains that natively encode it. Results showed that ExoS exerted unusually strong anti-internalization activity under conditions of expression in the effector-null background of strain PA103, often used to study T3SS effector activity. Inhibition of internalization was associated with T3SS hyperinducibility and ExoS delivery. PA103fleQmutation, preventing flagellar assembly, further reduced internalization but did so independently of ExoS. The results revealed intracellular T3SS expression by all strains and suggested that T3SS bistability influencesP. aeruginosainternalization. These findings reconcile controversies in the literature surroundingP. aeruginosainternalization and support the principle thatP. aeruginosais not exclusively an extracellular pathogen.

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