Modulation of NF-κB signalling by microbial pathogens

Rahman, Masmudur M.; McFadden, Grant

doi:10.1038/nrmicro2539

Cited by 350 publications

(378 citation statements)

References 167 publications

(141 reference statements)

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“…Various enteric pathogens inhibit signal transduction cascades at different points in the NF-kB signal transduction cascade (Rahman & McFadden, 2011). Shigella flexneri, for example, expresses a virulence factor, OspG, which prevents ubiquitination of phospho-IkBa, thereby negatively controlling innate immune responses (Kim et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Enterohaemorrhagic, but not enteropathogenic, Escherichia coli infection of epithelial cells disrupts signalling responses to tumour necrosis factor-alpha

Gareau

Brenner

et al. 2011

Microbiology

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Enterohaemorrhagic Escherichia coli (EHEC), serotype O157 : H7 is a non-invasive, pathogenic bacterium that employs a type III secretion system (T3SS) to inject effector proteins into infected cells. In this study, we demonstrate that EHEC blocks tumour necrosis factor-alpha (TNFa)-induced NF-kB signalling in infected epithelial cells. HEK293T and INT407 epithelial cells were challenged with EHEC prior to stimulation with TNFa. Using complementary techniques, stimulation with TNFa caused activation of NF-kB, as determined by luciferase reporter assay (increase in gene expression), Western blotting (phosphorylation of IkBa), immunofluorescence (p65 nuclear translocation) and immunoassay (CXCL-8 secretion), and each was blocked by EHEC O157 : H7 infection. In contrast, subversion of host cell signalling was not observed following exposure to either enteropathogenic E. coli, strain E2348/69 (O127 : H6) or the laboratory E. coli strain HB101. Heat-killed EHEC had no effect on NF-kB activation by TNFa. Inhibition was mediated, at least in part, by Shiga toxins and by the O157 plasmid, but not by the T3SS or flagellin, as demonstrated by using isogenic mutant strains. These findings indicate the potential for developing novel therapeutic targets to interrupt the infectious process.

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Section: Discussionmentioning

confidence: 99%

Enterohaemorrhagic, but not enteropathogenic, Escherichia coli infection of epithelial cells disrupts signalling responses to tumour necrosis factor-alpha

Gareau

Brenner

et al. 2011

Microbiology

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“…Given the important contribution of the NF-kB and MAPK signaling pathways in activating host innate immune responses, microbes have evolved a variety of strategies to inhibit activation of those signaling pathways (27)(28)(29)(30). To define the potential role of M. tuberculosis Mce3E in modulating host innate immunity as well as to identify the specific signaling pathways it targets, we examined the effects of M. tuberculosis Mce3E on activation of the NF-kB and MAPK signaling pathways.…”

Section: Inhibition Of the Erk Pathway By M Tuberculosis Mce3ementioning

confidence: 99%

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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“…The immune system has evolved a variety of receptors to recognize invading microorganisms (pathogens, bacteria and viruses) which result activation of NF-κB trafficking by gene regulation reported by Rahman et al (2011). In contrast, (Fig.…”

Section: Nf-κb Versus the Iκb Family As Master Regulatormentioning

confidence: 87%

A New Paradigm to Mitigate Osteosarcoma by Regulation of MicroRNAs and Suppression of the NF-κB Signaling Cascade

Mongre¹,

Sodhi²,

Ghosh³

et al. 2014

Development &Amp; Reproduciton

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Modulation of NF-κB signalling by microbial pathogens

Cited by 350 publications

References 167 publications

Enterohaemorrhagic, but not enteropathogenic, Escherichia coli infection of epithelial cells disrupts signalling responses to tumour necrosis factor-alpha

Enterohaemorrhagic, but not enteropathogenic, Escherichia coli infection of epithelial cells disrupts signalling responses to tumour necrosis factor-alpha

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

A New Paradigm to Mitigate Osteosarcoma by Regulation of MicroRNAs and Suppression of the NF-κB Signaling Cascade

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