A Burkholderia Type VI Effector Deamidates Rho GTPases to Activate the Pyrin Inflammasome and Trigger Inflammation

Aubert, Daniel; Xu, Hao; Yang, Jia Lin; Shi, Xuyan; Gao, Wenqing; Li, Lin; Bisaro, Fabiana; Chen, She; Valvano, Miguel A.; Shao, Feng

doi:10.1016/j.chom.2016.04.004

Cited by 151 publications

(160 citation statements)

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“…Because the PYRIN inflammasome also plays a role in the detection of B. cenocepacia in human and mouse macrophages [20,31,32], we next compared B. cenocepacia -induced CASP4 expression and the activation of CASP1 in WT, mefv −/- , and casp4 −/- macrophages at 6 h post infection via immunoblot. Expression of CASP4 in response to B. cenocepacia was markedly induced in WT and mefv −/- macrophages (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The T6SS of B. cenocepacia is essential for intracellular pathogenicity [19,32]. Accordingly, T6SS deficiency led to enhanced phagocytosis and the impairment of bacterial replication in WT macrophages (Fig S4B and C).…”

Section: Resultsmentioning

confidence: 99%

“…casp4 −/- macrophages also exhibit significantly lower amounts of active RHOA and inactive CFL1, even under basal conditions [25]. In addition, the B. cenocepacia T6SS effector TecA mediates the deamidation of RHOA in murine cells [32]. RHOA is well known for its ability to induce actin-derived stress fibers and focal adhesions [61], and it also promotes the activation of LIM kinases, which inhibit CFL1 via phosphorylation [62,63].…”

Section: Discussionmentioning

confidence: 99%

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CASP4/caspase-11 promotes autophagosome formation in response to bacterial infection

Krause¹,

Caution²,

Badr³

et al. 2018

Autophagy

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CASP4/caspase-11-dependent inflammasome activation is important for the clearance of various Gram-negative bacteria entering the host cytosol. Additionally, CASP4 modulates the actin cytoskeleton to promote the maturation of phagosomes harboring intracellular pathogens such as Legionella pneumophila but not those enclosing nonpathogenic bacteria. Nevertheless, this non-inflammatory role of CASP4 regarding the trafficking of vacuolar bacteria remains poorly understood. Macroautophagy/autophagy, a catabolic process within eukaryotic cells, is also implicated in the elimination of intracellular pathogens such as Burkholderia cenocepacia. Here we show that CASP4-deficient macrophages exhibit a defect in autophagosome formation in response to B. cenocepacia infection. The absence of CASP4 causes an accumulation of the small GTPase RAB7, reduced colocalization of B. cenocepacia with LC3 and acidic compartments accompanied by increased bacterial replication in vitro and in vivo. Together, our data reveal a novel role of CASP4 in regulating autophagy in response to B. cenocepacia infection.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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CASP4/caspase-11 promotes autophagosome formation in response to bacterial infection

Krause¹,

Caution²,

Badr³

et al. 2018

Autophagy

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show abstract

“…A well-established function of the T6SSs is to compete against rival bacteria in polymicrobial environments by delivering "antibacterial" toxins such as cell-wall-degrading enzymes, nucleases, and membrane-targeting enzymes, into target competitor bacterial cells (24)(25)(26)(27). Moreover, some T6SSs associated with pathogens have been reported to be involved in bacterial pathogenesis by translocating "antieukaryotic" effectors into eukaryotic cells to modulate host immunity and inflammation (28)(29)(30)(31). The well-characterized antieukaryotic effectors are several "evolved" VgrG proteins and non-VgrG phospholipases and deamidases (28)(29)(30)(31).…”

mentioning

confidence: 99%

“…Moreover, some T6SSs associated with pathogens have been reported to be involved in bacterial pathogenesis by translocating "antieukaryotic" effectors into eukaryotic cells to modulate host immunity and inflammation (28)(29)(30)(31). The well-characterized antieukaryotic effectors are several "evolved" VgrG proteins and non-VgrG phospholipases and deamidases (28)(29)(30)(31). Recently, we reported that the T6SS-4 from Yersinia pseudotuberculosis was involved in zinc transport via secretion of the zincchelating effector YezP into medium (32).…”

mentioning

confidence: 99%

Manganese scavenging and oxidative stress response mediated by type VI secretion system in Burkholderia thailandensis

Zhao

Burkinshaw

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

198

186

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Type VI secretion system (T6SS) is a versatile protein export machinery widely distributed in Gram-negative bacteria. Known to translocate protein substrates to eukaryotic and prokaryotic target cells to cause cellular damage, the T6SS has been primarily recognized as a contact-dependent bacterial weapon for microbe-host and microbial interspecies competition. Here we report contact-independent functions of the T6SS for metal acquisition, bacteria competition, and resistance to oxidative stress. We demonstrate that the T6SS-4 in Burkholderia thailandensis is critical for survival under oxidative stress and is regulated by OxyR, a conserved oxidative stress regulator. The T6SS-4 is important for intracellular accumulation of manganese (Mn 2+ ) under oxidative stress. Next, we identified a T6SS-4-dependent Mn 2+ -binding effector TseM, and its interacting partner MnoT, a Mn 2+ -specific TonB-dependent outer membrane transporter. Similar to the T6SS-4 genes, expression of mnoT is regulated by OxyR and is induced under oxidative stress and low Mn 2+ conditions. Both TseM and MnoT are required for efficient uptake of Mn 2+ across the outer membrane under Mn 2+ -limited and -oxidative stress conditions. The TseM-MnoT-mediated active Mn 2+ transport system is also involved in contact-independent bacteria-bacteria competition and bacterial virulence. This finding provides a perspective for understanding the mechanisms of metal ion uptake and the roles of T6SS in bacteria-bacteria competition.

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Function and mechanism of the pyrin inflammasome

2017

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Pyrin, encoded by the MEFV gene, is an intracellular pattern recognition receptor that assembles inflammasome complexes in response to pathogen infections. Mutations in the MEFV gene have been linked to autoinflammatory diseases such as familial Mediterranean fever (FMF) or pyrin-associated autoinflammation with neutrophilic dermatosis (PAAND). Recent insights have now revealed how pyrin is activated during infection, providing a molecular basis for the understanding of such disease-causing mutations in pyrin. Interestingly, pyrin does not directly recognize molecular patterns (pathogenor host-derived danger molecules), but rather responds to disturbances in cytoplasmic homeostasis caused by the infection. In the case of pyrin, these perturbations, recently defined as 'homeostasis-altering molecular processes' (HAMPs), are processes leading to the inactivation of the RhoA GTPase. This review attempts to combine early observation and findings with the most recent discoveries on how pyrin detects inactivation of RhoA to shed light on the function and mechanism of pyrin activation.Keywords: FMF r Inflammasome r MEFV r Pyrin r Pyroptosis IntroductionThe observation of inherited pathogenic periodic fevers and inflammation prevalent in Mediterranean regions led to first clinical descriptions of a disease now known as familial Mediteranean fever (FMF) [1], one of the most common hereditary autoinflammatory syndromes. Further studies revealed that FMF, was an autosomal recessive disease associated with mutations in the MEFV gene, which encodes a protein named pyrin [2,3]. Pyrin belongs to the group of cytosolic pattern recognition receptors (PRRs) that control innate immune responses upon the detection of pathogen or host derived danger signals, so called pathogen/danger-associated molecular patterns (PAMPs/DAMPs). Upon activation, several of these receptors, including pyrin, assemble multiprotein signaling complexes called inflammasomes, which recruit and activate caspase-1, a proinflammatory protease [4]. Active caspase-1 drives inflammation by promoting the proteolytic maturation and secretion of cytokines Correspondence: Dr. Petr Broz e-mail: petr.broz@unil.ch such as interleukin (IL)-1β and IL-18, and by initiating a necrotic type of cell death known as pyroptosis. Pyroptosis is caused by the Gasdermin-D (GSDMD) protein which, upon cleavage by caspase-1, forms large permeability pores in the cellular plasma membrane [5][6][7][8][9].Recent literature provides new perspectives on the type of ligands that activate pyrin and on its unusual activation mechanism which is distinct from other well-characterized inflammasome forming PRRs. Moreover, new studies also find evidence for a unique participation of the cytoskeleton during pyrin inflammasome activation. This review sets out to integrate previous observations and discoveries on the pyrin inflammasome with most recent findings. Additionally, we attempt to pinpoint shortcomings and potential gaps in the literature which will need to be addressed in the future.Protein ...

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A Burkholderia Type VI Effector Deamidates Rho GTPases to Activate the Pyrin Inflammasome and Trigger Inflammation

Cited by 151 publications

References 63 publications

CASP4/caspase-11 promotes autophagosome formation in response to bacterial infection

CASP4/caspase-11 promotes autophagosome formation in response to bacterial infection

Manganese scavenging and oxidative stress response mediated by type VI secretion system in Burkholderia thailandensis

Function and mechanism of the pyrin inflammasome

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