Targeting Rac1 by the Yersinia Effector Protein YopE Inhibits Caspase-1-mediated Maturation and Release of Interleukin-1β

Schotte, Peter; Denecker, Geertrui; Broeke, A Van Den; Vandenabeele, Peter; Cornelis, Guy R.; Beyaert, Rudi

doi:10.1074/jbc.m401245200

Cited by 127 publications

(131 citation statements)

References 56 publications

(69 reference statements)

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“…6A). Consistent with previous reports on the mutual induction of GTPases (27,28), we demonstrated that all three tested GTPase inhibitors significantly suppressed IL-22 secretion in differentiated Th17 cells. Rac and Rho kinase inhibitors suppressed IL-21, simvastatin-inhibited IL-17F was replicated by Rab and Rho-kinase inhibitor, whereas simvastatin-inhibited IL-17A secretion was only replicated by the Rho kinase/ROCKspecific inhibitor Y-27632 (Fig.…”

Section: Simvastatin Inhibits Irf4 Expression and Th17 Cell Differentsupporting

confidence: 81%

Simvastatin Inhibits IFN Regulatory Factor 4 Expression and Th17 Cell Differentiation in CD4+ T Cells Derived from Patients with Multiple Sclerosis

Zhang

Tao

Troiani

et al. 2011

The Journal of Immunology

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Subsequent to the clinical trial of simvastatin in patients with relapsing remitting multiple sclerosis (RR MS), which demonstrated the ability of simvastatin to inhibit new inflammatory CNS lesion formation, the current in vitro study has characterized the mechanisms through which simvastatin inhibits Th17 cell differentiation. The anti-inflammatory effects of statins are mediated by the inhibition of isoprenylation, which ensures proper membrane insertion and function of proteins. Small GTPases, involved in multiple signal transduction pathways, are the key targets for isoprenylation. We report that simvastatin, one of the most hydrophobic statins with good CNS penetration, inhibited Th17 cell differentiation and IL-17A, IL-17F, IL-21, and IL-22 secretion in in vitro-differentiated naive CD4+ T cells from RR MS patients. Simvastatin exerted a less prominent effect on the cells from healthy controls, as it inhibited only IL-17F secretion. The inhibition of Th17 cell differentiation was mediated via inhibition of IFN regulatory factor 4 (IRF4) expression, which was identified as a key transcription factor for human Th17 cell differentiation using both IRF4 gene knockdown and overexpression experiments. In studies addressing which isoprenylation pathway—geranylgeranylation or farnesylation—is inhibited by simvastatin, we demonstrated that the geranylgeranyl transferase inhibitor replicated the effect of simvastatin. Selective inhibition of geranylgeranylated RhoA-associated kinase replicated the effect of simvastatin on the inhibition of IRF4 expression and IL-17A, IL-17F, IL-21, and IL-22 secretion, presenting a promising new therapeutic approach for this disabling disease.

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Section: Simvastatin Inhibits Irf4 Expression and Th17 Cell Differentsupporting

confidence: 81%

Simvastatin Inhibits IFN Regulatory Factor 4 Expression and Th17 Cell Differentiation in CD4+ T Cells Derived from Patients with Multiple Sclerosis

Zhang

Tao

Troiani

et al. 2011

The Journal of Immunology

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“…In contrast, YopT inactivates Rho GTPases by proteolytically removing the Cterminal prenyl membrane anchor by which they are attached to the plasma membrane. Although it is currently unclear how Yop effector proteins and cytoskeletal processes may interfere with inflammasome signaling, inactivation of the Rho GTPase Rac1 with dominant-negative proteins and chemical inhibitors suggested a critical role for this Rho GTPase in caspase-1 activation and IL-1b secretion (35). Nevertheless, the precise molecular events linking YopE and YopT to inflammasome inhibition await further analysis.…”

Section: Modulation Of Inflammasome Activation By Bacterial Virulencementioning

confidence: 99%

“…For instance, enteropathogenic Yersinia enterocolitica injects virulence factors called Yop proteins into the host cell cytosol through a dedicated type III secretion system. Among these effector proteins, YopE and YopT inhibit caspase-1 activation and the subsequent secretion of mature IL-1b (35). These Yop proteins are well-known negative regulators of Rho GTPases and Rho-mediated processes such as cytoskeletal reorganization and phagocytosis.…”

Section: Modulation Of Inflammasome Activation By Bacterial Virulencementioning

confidence: 99%

Modulation of Inflammasome Pathways by Bacterial and Viral Pathogens

Lamkanfi

Dixit²

2011

The Journal of Immunology

207

175

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Inflammasomes are emerging as key regulators of the host response against microbial pathogens. These cytosolic multiprotein complexes recruit and activate the cysteine protease caspase-1 when microbes invade sterile tissues or elicit cellular damage. Inflammasome-activated caspase-1 induces inflammation by cleaving the proinflammatory cytokines IL-1β and IL-18 into their biologically active forms and by releasing the alarmin HMGB1 into the extracellular milieu. Additionally, inflammasomes counter bacterial replication and clear infected immune cells through an inflammatory cell death program termed pyroptosis. As a countermeasure, bacterial and viral pathogens evolved virulence factors to antagonize inflammasome pathways. In this review, we discuss recent progress on how inflammasomes contribute to host defense against bacterial and viral pathogens, and we review how viruses and bacteria modulate inflammasome function to their benefit.

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“…Among the Yersiniaencoded YOP effector proteins, both YopE and YopT have been shown to interfere with the caspase-1 mediated maturation of proIL-1β in macrophages (Table 1). This outcome is achieved by impeding the autoproteolytic activation of caspase-1 through a mechanism both related to and dependent on the ability of these proteins to inhibit the key Rho GTPases involved in cytoskeletal reorganization, namely, Rac-1 and LIM kinase-1 [102]. Another Yop protein, YopP, a bacterial modulator of NF-κB activity, can also regulate IL-1β production by inhibiting NF-κB mediated transcriptional events [102].…”

Section: Bacterial Strategies For Modulating the Inflammasomementioning

confidence: 99%

“…This outcome is achieved by impeding the autoproteolytic activation of caspase-1 through a mechanism both related to and dependent on the ability of these proteins to inhibit the key Rho GTPases involved in cytoskeletal reorganization, namely, Rac-1 and LIM kinase-1 [102]. Another Yop protein, YopP, a bacterial modulator of NF-κB activity, can also regulate IL-1β production by inhibiting NF-κB mediated transcriptional events [102]. Conversely, the type III secretion systems of Salmonella and Shigella result in activation of caspase-1 in infected macrophages, as demonstrated for the SipB protein of S. typhimurium and the IpaB protein of Shigella flexneri [41,42].…”

Section: Bacterial Strategies For Modulating the Inflammasomementioning

confidence: 99%

Strategies that modulate inflammasomes—insights from host–pathogen interactions

2007

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/npsi/ctrl?action=rtdoc&an=8934216&lang=en http://nparc.cisti-icist.nrc-cnrc.gc.ca/npsi/ctrl?action=rtdoc&an=8934216&lang=frAccess and use of this website and the material on it are subject to the Terms and Conditions set forth at http://nparc.cisti-icist.nrc-cnrc.gc.ca/npsi/jsp/nparc_cp.jsp?lang=en NRC Publications Archive Archives des publications du CNRCThis publication could be one of several versions: author's original, accepted manuscript or the publisher's version. / La version de cette publication peut être l'une des suivantes : la version prépublication de l'auteur, la version acceptée du manuscrit ou la version de l'éditeur. For the publisher's version, please access the DOI link below./ Pour consulter la version de l'éditeur, utilisez le lien DOI ci-dessous.http://dx.doi.org/10.1007/s00281-007-0080-5Seminars in Immunopathology, 29, 3, pp. 261-274, 2007 Strategies that modulate inflammasomes-insights from host-pathogen interactions Johnston, James B; Rahman, Masmudur; McFadden, Grant Abstract The innate immune system is a dynamic and complex network for recognizing and responding to cellular insult or tissue damage after infection or injury. The primary effector mechanism of innate immunity is the generation of acute and chronic inflammatory responses through regulation of the processing and activation of proinflammatory caspases, particularly caspase 1, and cytokines, most notably IL-1β and IL-18. Inflammasomes, cytosolic multi-protein complexes that function as molecular scaffolds for caspase activation, have recently emerged as the pivotal mechanism by which host innate immune and inflammatory responses are regulated. In this review, we investigate the mechanisms by which inflammasomes are modulated, both by endogenous host systems and by microbial pathogens.

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Targeting Rac1 by the Yersinia Effector Protein YopE Inhibits Caspase-1-mediated Maturation and Release of Interleukin-1β

Cited by 127 publications

References 56 publications

Simvastatin Inhibits IFN Regulatory Factor 4 Expression and Th17 Cell Differentiation in CD4+ T Cells Derived from Patients with Multiple Sclerosis

Simvastatin Inhibits IFN Regulatory Factor 4 Expression and Th17 Cell Differentiation in CD4+ T Cells Derived from Patients with Multiple Sclerosis

Modulation of Inflammasome Pathways by Bacterial and Viral Pathogens

Strategies that modulate inflammasomes—insights from host–pathogen interactions

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