<scp><i>Y</i></scp><i>ersinia pseudotuberculosis</i> <scp>YopD</scp>mutants that genetically separate effector protein translocation from host membrane disruption

Adams, Walter; Morgan, Joe P.; Kwuan, Laura; Auerbuch, Victoria

doi:10.1111/mmi.12970

Cited by 7 publications

(5 citation statements)

References 59 publications

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“…Additional bacterial factors are important for fine-tuning effector translocation. The Yersinia cytotoxic necrotizing factor-γ produced by certain strains activates Rac-[27] and Rho-GTPases [28] to enhance Yop translocation into target immune cells, while structure-function studies reveal regions within the transolocon component YopD to be important for effector delivery [29–31]. …”

Section: Later Interactions Of Yersinia With Host Cells-important Formentioning

confidence: 99%

Yersinia versus host immunity: how a pathogen evades or triggers a protective response

Chung

Bliska

2016

Current Opinion in Microbiology

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The human pathogenic Yersinia species cause diseases that represent a significant source of morbidity and mortality. Despite this, specific mechanisms underlying Yersinia pathogenesis and protective host responses remain poorly understood. Recent studies have shown that Yersinia disrupt cell death pathways, perturb inflammatory processes and exploit immune cells to promote disease. The ensuing host responses following Yersinia infection include coordination of innate and adaptive immune responses in an attempt to control bacterial replication. Here, we highlight current advances in our understanding of the interactions between the pathogenic yersiniae and host cells, as well as the protective host responses mobilized to counteract these pathogens. Together, these studies enhance our understanding of Yersinia pathogenesis and highlight the ongoing battle between host and microbe.

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Section: Later Interactions Of Yersinia With Host Cells-important Formentioning

confidence: 99%

Yersinia versus host immunity: how a pathogen evades or triggers a protective response

Chung

Bliska

2016

Current Opinion in Microbiology

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“…Additional evidence demonstrates that the translocon pore, rather than simply a conduit for effector secretion, functions in an active capacity to regulate effector secretion [7, 10]. Discrete mutations in translocon pore proteins have been identified that do not alter the efficiency of translocon pore formation but restrict the efficiency of docking or effector translocation [7, 14], which shows that translocon pore formation per se is not sufficient for T3SS function.…”

Section: Introductionmentioning

confidence: 99%

Activation of Shigella flexneri type 3 secretion requires a host-induced conformational change to the translocon pore

et al. 2019

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Type 3 secretion systems (T3SSs) are conserved bacterial nanomachines that inject virulence proteins (effectors) into eukaryotic cells during infection. Due to their ability to inject heterologous proteins into human cells, these systems are being developed as therapeutic delivery devices. The T3SS assembles a translocon pore in the plasma membrane and then docks onto the pore. Docking activates effector secretion through the pore and into the host cytosol. Here, using Shigella flexneri, a model pathogen for the study of type 3 secretion, we determined the molecular mechanisms by which host intermediate filaments trigger docking and enable effector secretion. We show that the interaction of intermediate filaments with the translocon pore protein IpaC changed the pore’s conformation in a manner that was required for docking. Intermediate filaments repositioned residues of the Shigella pore protein IpaC that are located on the surface of the pore and in the pore channel. Restricting these conformational changes blocked docking in an intermediate filament-dependent manner. These data demonstrate that a host-induced conformational change to the pore enables T3SS docking and effector secretion, providing new mechanistic insight into the regulation of type 3 secretion.

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“…Knowledge is limited concerning the stepwise biogenesis of the T3SS translocon pore and its relationship toward effector protein translocation. Encouragingly, recent mutagenesis studies of the YopD translocator have been able to genetically demarcate discrete functional domains [ 29 , 32 , 33 , 51 , 59–61 ]. This hints at the possibility that YopD mutants could be generated that have targeted deficits in one or a few phenotypes in isolation from all others.…”

Section: Discussionmentioning

confidence: 99%

Macrophage innate immune responses delineate between defective translocon assemblies produced by Yersinia pseudotuberculosis YopD mutants

Farag,

Francis,

Gurung

et al. 2023

Virulence

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Translocon pores formed in the eukaryotic cell membrane by a type III secretion system facilitate the translocation of immune-modulatory effector proteins into the host cell interior. The YopB and YopD proteins produced and secreted by pathogenic Yersinia spp. harboring a virulence plasmid-encoded type III secretion system perform this pore-forming translocator function. We had previously characterized in vitro T3SS function and in vivo pathogenicity of a number of strains encoding sited-directed point mutations in yopD . This resulted in the classification of mutants into three different classes based upon the severity of the phenotypic defects. To investigate the molecular and functional basis for these defects, we explored the effectiveness of RAW 264.7 cell line to respond to infection by representative YopD mutants of all three classes. Signature cytokine profiles could separate the different YopD mutants into distinct categories. The activation and suppression of certain cytokines that function as central innate immune response modulators correlated well with the ability of mutant bacteria to alter anti-phagocytosis and programmed cell death pathways. These analyses demonstrated that sub-optimal translocon pores impact the extent and magnitude of host cell responsiveness, and this limits the capacity of pathogenic Yersinia spp. to fortify against attack by both early and late arms of the host innate immune response.

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Yersinia pseudotuberculosis YopDmutants that genetically separate effector protein translocation from host membrane disruption

Cited by 7 publications

References 59 publications

Yersinia versus host immunity: how a pathogen evades or triggers a protective response

Yersinia versus host immunity: how a pathogen evades or triggers a protective response

Activation of Shigella flexneri type 3 secretion requires a host-induced conformational change to the translocon pore

Macrophage innate immune responses delineate between defective translocon assemblies produced by Yersinia pseudotuberculosis YopD mutants

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