Current activities of the Yersinia effector protein YopM

Höfling, Sabrina; Grabowski, Benjamin; Norkowski, Stefanie; Schmidt, M. Alexander; Rüter, Christian

doi:10.1016/j.ijmm.2015.03.009

Cited by 18 publications

(9 citation statements)

References 77 publications

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“…Although inhibition of the pyrin inflammasome appears to be a major virulence function, there exist additional mechanisms by which YopM promotes pathogenesis (Hofling et al, 2015). For example, YopM has been shown to autonomously translocate into both the cytosol and nucleus of eukaryotic cells and can also suppress transcription of the proinflammatory cytokine TNFα (Ruter et al, 2010, Scharnert et al, 2013, Hofling et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

The Yersinia Virulence Factor YopM Hijacks Host Kinases to Inhibit Type III Effector-Triggered Activation of the Pyrin Inflammasome

Chung

Park

Zheng

et al. 2016

Cell Host & Microbe

174

184

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Summary Pathogenic Yersinia, including Y. pestis, the agent of plague in humans, and Y. pseudotuberculosis, the related enteric pathogen, deliver virulence effectors into host cells via a prototypical type III secretion system to promote pathogenesis. These effectors, termed Yersinia outer proteins (Yops), modulate multiple host signaling responses. Studies in Y. pestis and Y. pseudotuberculosis have shown that YopM suppresses infection-induced inflammasome activation, however the underlying molecular mechanism is largely unknown. Here we show that YopM specifically restricts the pyrin inflammasome, which is triggered by the RhoA-inactivating enzymatic activities of YopE and YopT, in Y. pseudotuberculosis-infected macrophages. The attenuation of a yopM mutant is fully reversed in pyrin knock-out mice, demonstrating that YopM inhibits pyrin to promote virulence. Mechanistically, YopM recruits and activates the host kinases PRK1 and PRK2 to negatively regulate pyrin by phosphorylation. These results show how a virulence factor can hijack host kinases to inhibit effector-triggered pyrin inflammasome activation.

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Section: Discussionmentioning

confidence: 99%

The Yersinia Virulence Factor YopM Hijacks Host Kinases to Inhibit Type III Effector-Triggered Activation of the Pyrin Inflammasome

Chung

Park

Zheng

et al. 2016

Cell Host & Microbe

174

184

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“…In particular, two CPPs derived from the Y. enterocolitica effector protein YopM were employed and their functional properties were characterized. We had previously shown that the Y. enterocolitica-derived YopM protein can autonomously translocate into eukaryotic cells independently of the T3SS (28)(29)(30). Autonomously cell-penetrating recombinant YopM is functional and downregulates the expression of proinflammatory cytokines (4,34), suggesting a dual use of YopM as a delivery vehicle for cargo molecules and as a biological therapeutic for immunomodulation (31,32).…”

mentioning

confidence: 99%

Bacterium-Derived Cell-Penetrating Peptides Deliver Gentamicin To Kill Intracellular Pathogens

Gomarasca

Martins

Greune

et al. 2017

Antimicrob Agents Chemother

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Commonly used antimicrobials show poor cellular uptake and often have limited access to intracellular targets, resulting in low antimicrobial activity against intracellular pathogens. An efficient delivery system to transport these drugs to the intracellular site of action is needed. Cell-penetrating peptides (CPPs) mediate the internalization of biologically active molecules into the cytoplasm. Here, we characterized two CPPs, ␣1H and ␣2H, derived from the Yersinia enterocolitica YopM effector protein. These CPPs, as well as Tat (trans-activator of transcription) from HIV-1, were used to deliver the antibiotic gentamicin to target intracellular bacteria. The YopM-derived CPPs penetrated different endothelial and epithelial cells to the same extent as Tat. CPPs were covalently conjugated to gentamicin, and CPP-gentamicin conjugates were used to target infected cells to kill multiple intracellular Gram-negative pathogenic bacteria, including Escherichia coli K1, Salmonella enterica serovar Typhimurium, and Shigella flexneri. Taken together, CPPs show great potential as delivery vehicles for antimicrobial agents and may contribute to the generation of new therapeutic tools to treat infectious diseases caused by intracellular pathogens.

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“…The molecular contribution of YopM to Yersinia pathogenesis is still unclear; however, it has been shown to target immune cells to effect different immune cell populations of the spleen and liver of infected mice, downregulate proinflammatory responses, and upregulate the antiinflammatory cytokine, IL-10 [122][123][124][125] . IL-10 downregulates the production of proinflammatory cytokines by multiple innate immune cells, as well as regulates T cell function and proliferation [126] .…”

Section: Yopm Is Indispensable To Yersinia Virulencementioning

confidence: 99%

“…YopM was also shown to inhibit platelet aggregation [127] . Although YopM is required to enhance Yersinia virulence in mouse infection models, varying results suggest that the route of infection and mouse strain used affects the reported contribution of YopM to Yersinia pathogenesis [122] . Moreover, this could also be attributed to the LRR motifs of the YopM variants, as well as the natural route of infection of the pathogenic Yersinia species.…”

Section: Yopm Is Indispensable To Yersinia Virulencementioning

confidence: 99%

Yersiniatype III effectors perturb host innate immune responses

Pha

Navarro

2016

WJBC

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The innate immune system is the first line of defense against invading pathogens. Innate immune cells recognize molecular patterns from the pathogen and mount a response to resolve the infection. The production of proinflammatory cytokines and reactive oxygen species, phagocytosis, and induced programmed cell death are processes initiated by innate immune cells in order to combat invading pathogens. However, pathogens have evolved various virulence mechanisms to subvert these responses. One strategy utilized by Gram-negative bacterial pathogens is the deployment of a complex machine termed the type Ⅲ secretion system (T3SS). The T3SS is composed of a syringe-like needle structure and the effector proteins that are injected directly into a target host cell to disrupt a cellular response. The Multisite autophosphorylation by YpkA to activate its kinase domain was also shown and postulated to serve as a mechanism to bypass regulation by host phosphatases. In addition, novel Yersinia effector protein targets, such as caspase-1, and signaling pathways including activation of the inflammasome were identified. In this review, we summarize the recent discoveries made on Yersinia effector proteins and their contribution to Yersinia pathogenesis.

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Current activities of the Yersinia effector protein YopM

Cited by 18 publications

References 77 publications

The Yersinia Virulence Factor YopM Hijacks Host Kinases to Inhibit Type III Effector-Triggered Activation of the Pyrin Inflammasome

The Yersinia Virulence Factor YopM Hijacks Host Kinases to Inhibit Type III Effector-Triggered Activation of the Pyrin Inflammasome

Bacterium-Derived Cell-Penetrating Peptides Deliver Gentamicin To Kill Intracellular Pathogens

Yersiniatype III effectors perturb host innate immune responses

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