A Yersinia Effector Protein Promotes Virulence by Preventing Inflammasome Recognition of the Type III Secretion System

Brodsky, Igor E.; Palm, Noah W.; Sadanand, Saheli; Ryndak, Michelle B.; Sutterwala, Fayyaz S.; Flavell, Richard A.; Bliska, James B.; Medzhitov, Ruslan

doi:10.1016/j.chom.2010.04.009

Cited by 269 publications

(366 citation statements)

References 59 publications

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“…The activity of the T3SS itself, as well as the activity of translocated effectors, triggers inflammasome activation, which promotes Yersinia clearance in vivo (36,80). However, Yersinia also inhibits inflammasome activation through the activities of YopK and YopM (36,38,39).…”

Section: Discussionmentioning

confidence: 99%

“…Successful bacterial pathogens have thus evolved strategies to mask these virulence factors from detection or to blunt the host response that is initiated (72)(73)(74). Indeed, a number of studies in several different systems have revealed that immune sensing of virulence factor activity promotes pathogen clearance (36,(75)(76)(77)(78)(79).…”

Section: Discussionmentioning

confidence: 99%

“…YopM interferes with YopE-and YopT-mediated activation of the pyrin inflammasome by binding to protein kinase C-related kinases (PRKs) and promoting PRK-dependent phosphorylation and inactivation of pyrin (37). Interestingly, Yersinia pseudotuberculosis and Yersinia pestis YopK mutants are unable to prevent inflammasome activation despite the presence of YopM, indicating that YopM and YopK block the inflammasome via distinct, nonredundant mechanisms (36,38,40).…”

mentioning

confidence: 99%

“…Pathogenic Yersinia bacteria inject Yop proteins that modulate a number of fundamental cellular processes, which collectively promote Yersinia virulence. Notably, two Yersinia proteins, YopM and YopK, prevent inflammasome activation in Yersinia-infected cells (36)(37)(38)(39). YopM interferes with YopE-and YopT-mediated activation of the pyrin inflammasome by binding to protein kinase C-related kinases (PRKs) and promoting PRK-dependent phosphorylation and inactivation of pyrin (37).…”

mentioning

confidence: 99%

“…YopK is translocated into host cells and regulates T3SS translocation by interacting with the proteins YopB and YopD (36,41). YopB and YopD are both integral transmembrane proteins and form the pore, or translocon complex, through which other Yops are injected into the host cell.…”

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confidence: 99%

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Guanylate Binding Proteins Regulate Inflammasome Activation in Response to Hyperinjected Yersinia Translocon Components

et al. 2017

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Gram-negative bacterial pathogens utilize virulence-associated secretion systems to inject, or translocate, effector proteins into host cells to manipulate cellular processes and promote bacterial replication. However, translocated bacterial products are sensed by nucleotide binding domain and leucine-rich repeat-containing proteins (NLRs), which trigger the formation of a multiprotein complex called the inflammasome, leading to secretion of interleukin-1 (IL-1) family cytokines, pyroptosis, and control of pathogen replication. Pathogenic Yersinia bacteria inject effector proteins termed Yops, as well as pore-forming proteins that comprise the translocon itself, into target cells. The Yersinia translocation regulatory protein YopK promotes bacterial virulence by limiting hyperinjection of the translocon proteins YopD and YopB into cells, thereby limiting cellular detection of Yersinia virulence activity. How hyperinjection of translocon proteins leads to inflammasome activation is currently unknown. We found that translocated YopB and YopD colocalized with the late endosomal/lysosomal protein LAMP1 and that the frequency of YopD and LAMP1 association correlated with the level of caspase-1 activation in individual cells. We also observed colocalization between YopD and Galectin-3, an indicator of endosomal membrane damage. Intriguingly, YopK limited the colocalization of Galectin-3 with YopD, suggesting that YopK limits the induction or sensing of endosomal membrane damage by components of the type III secretion system (T3SS) translocon. Furthermore, guanylate binding proteins (GBPs) encoded on chromosome 3 (Gbp Chr3 ), which respond to pathogen-induced damage or alteration of host membranes, were necessary for inflammasome activation in response to hyperinjected YopB/-D. Our findings indicate that lysosomal damage by Yersinia translocon proteins promotes inflammasome activation and implicate GBPs as key regulators of this process.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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confidence: 99%

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Guanylate Binding Proteins Regulate Inflammasome Activation in Response to Hyperinjected Yersinia Translocon Components

et al. 2017

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Yersinia

Guern¹,

Pizarro‐Cerdá²

2022

Pathogenesis of Bacterial Infections in Animals

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NLRC4 biology in immunity and inflammation

Andrade

Zamboni

2020

Journal of Leukocyte Biology

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Inflammasomes are cytosolic multiprotein complexes that sense microbial infections or host cell damage, triggering cytokine production and a proinflammatory form of cell death, called pyroptosis. Whereas pyroptosis and cytokine production may often promote host resistance to infections, uncontrolled inflammasome activation leads to autoinflammatory diseases in humans. Among the multiple inflammasomes described, the neuronal apoptosis inhibitory protein/nucleotide-binding domain leucine-rich repeat-containing protein family caspase activation and recruitment domaincontaining protein 4 (NLRC4) inflammasome emerged as a critical component for the restriction of bacterial infections. Accordingly, our understanding of this inflammasome advanced remarkably over the last 10 yr, expanding our knowledge about ligand-receptor interaction; cryo-EM structure; and downstream effectors and substrates, such as gasdermin-D, caspase-1, caspase-8, and caspase-7. In this review, we discuss recent advances on the biology of the NLRC4 inflammasome, in terms of structure and activation mechanisms, importance in bacterial and nonbacterial diseases, and the identification of NLRC4 gain-of-function mutations leading to NLRC4-associated autoinflammatory diseases in humans.

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A Yersinia Effector Protein Promotes Virulence by Preventing Inflammasome Recognition of the Type III Secretion System

Cited by 269 publications

References 59 publications

Guanylate Binding Proteins Regulate Inflammasome Activation in Response to Hyperinjected Yersinia Translocon Components

Guanylate Binding Proteins Regulate Inflammasome Activation in Response to Hyperinjected Yersinia Translocon Components

Yersinia

NLRC4 biology in immunity and inflammation

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