Cytotoxic Necrotizing Factor-Y Boosts Yersinia Effector Translocation by Activating Rac Protein

Wolters, Manuel; Boyle, Erin C.; Lardong, Kerstin; Trülzsch, Konrad; Steffen, Anika; Rottner, Klemens; Ruckdeschel, Klaus; Aepfelbacher, Martin

doi:10.1074/jbc.m112.448662

Cited by 30 publications

(33 citation statements)

References 68 publications

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“…In addition to thermoregulated transcription, they are under RNAT control. The cytotoxic necrotizing factor CNFγ acts as toxin and is an essential virulence determinant, as it modulates inflammatory responses and counteracts attack by innate immune effectors (36,37). Similar to YadA, the adhesin AilA promotes binding to and subsequent killing of neutrophils via type III secretion-mediated translocation of effector proteins into the target host cell and promotes resistance against complement-mediated killing (38)(39)(40)(41).…”

Section: Discussionmentioning

confidence: 99%

Temperature-responsive in vitro RNA structurome of Yersinia pseudotuberculosis

Righetti

Nuss

Twittenhoff

et al. 2016

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

136

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RNA structures are fundamentally important for RNA function. Dynamic, condition-dependent structural changes are able to modulate gene expression as shown for riboswitches and RNA thermometers. By parallel analysis of RNA structures, we mapped the RNA structurome of Yersinia pseudotuberculosis at three different temperatures. This human pathogen is exquisitely responsive to host body temperature (37°C), which induces a major metabolic transition. Our analysis profiles the structure of more than 1,750 RNAs at 25°C, 37°C, and 42°C. Average mRNAs tend to be unstructured around the ribosome binding site. We searched for 5′-UTRs that are folded at low temperature and identified novel thermoresponsive RNA structures from diverse gene categories. The regulatory potential of 16 candidates was validated. In summary, we present a dynamic bacterial RNA structurome and find that the expression of virulence-relevant functions in Y. pseudotuberculosis and reprogramming of its metabolism in response to temperature is associated with a restructuring of numerous mRNAs.RNA structure | RNA thermometer | temperature | virulence | translational control R NA structures play a pivotal role in the function of noncoding RNAs (ncRNAs) comprised of rRNAs, tRNAs, and small regulatory RNAs (sRNAs) and in the expression of proteincoding mRNAs. Structured segments affect the entire RNA life cycle from transcription, maturation, and translation to degradation and determine the specificity of interactions with other RNAs, proteins, or ligands. Although some RNAs, such as ribozymes and rRNAs, adopt rather stable secondary and tertiary structures, many regulatory RNA elements are dynamic and undergo structural rearrangements in the physiological temperature range. Well-known examples are metabolite-sensing riboswitches (1) and temperaturesensing RNA thermometers (RNATs) (2). Bacterial RNATs are usually located in the 5′-UTR or the intercistronic region (ICR) of an mRNA and differentially control translation of the downstream ORF in response to temperature (3). Typically, an RNAT folds into a structure that occludes the ribosome binding site (RBS). A temperature upshift liberates the RBS and allows the ribosome to bind and initiate translation. Structurally diverse RNATs are located upstream of many bacterial heat shock and virulence genes. Thermosensitive RNA structures playing a role in infection and host adaptation processes have been documented in Listeria monocytogenes (4), Yersinia pestis (5), Yersinia pseudotuberculosis (6), Leptospira interrogans (7), Shigella dysenteriae (8), Neisseria meningitidis (9), Pseudomonas aeruginosa (10), and Vibrio cholerae (11).In contrast to ligand-binding riboswitches, RNATs show poor, if any, conservation in sequence and structure. This diversity has hampered the in silico identification of novel RNATs, but recently developed genome-wide RNA structure-probing approaches offer new opportunities (12). Global structure probing maps the structures of the entire pool of expressed RNA molecules and provides a sna...

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Section: Discussionmentioning

confidence: 99%

Temperature-responsive in vitro RNA structurome of Yersinia pseudotuberculosis

Righetti

Nuss

Twittenhoff

et al. 2016

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

136

View full text Add to dashboard Cite

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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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“…It would be interesting to establish whether Yersinia promotes cell death in epithelial cells by targeting any of the identified molecules specifically. For example, Yersinia is already known to modify Cdc42 via its toxin CNF-gamma, which activates several other GTPases, and this is proposed to lead to stronger pro-inflammatory responses [55, 56]. Cdc42 and Ezrin (both present in our dataset) are GTPases involved in modification of actin cytoskeleton and they both regulate cell viability [57, 58].…”

Section: Resultsmentioning

confidence: 99%

“…Yersinia encodes YopO (YpkA) that mimics host guanidine nucleotide dissociation inhibitors, and it has affinity for Rac1 and RhoA but not for Cdc42 [62, 63]. Also, cytotoxic necrotizing factor-Y (CNF-gamma) activates Rac1 and Cdc42, but not RhoA [55]. Another interesting interaction found in the second identified protein network (Fig.…”

Section: Resultsmentioning

confidence: 99%

Analysis of differentially expressed proteins in Yersinia enterocolitica-infected HeLa cells

Alugubelly

Hercík

Kibler

et al. 2016

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics

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Yersinia enterocolitica is a facultative intracellular pathogen and a causative agent of yersiniosis, which can be contracted by ingestion of contaminated food. Yersinia secretes virulence factors to subvert critical pathways in the host cell. In this study we utilized shotgun label-free proteomics to study differential protein expression in epithelial cells infected with Yersinia enterocolitica. We identified a total of 551 proteins, amongst which 42 were downregulated (e.g. Prostaglandin E Synthase 3, POH-1 and Karyopherin alpha) and 22 were upregulated (e.g. Rab1c and RhoA) in infected cells. We validated some of these results by western blot analysis of proteins extracted from Caco-2 and HeLa cells. The proteomic dataset was used to identify host canonical pathways and molecular functions modulated by this infection in the host cells. This study constitutes a proteome of Yersinia-infected cells and can support new discoveries in the area of host-pathogen interactions.

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Cytotoxic Necrotizing Factor-Y Boosts Yersinia Effector Translocation by Activating Rac Protein

Cited by 30 publications

References 68 publications

Temperature-responsive in vitro RNA structurome of Yersinia pseudotuberculosis

Temperature-responsive in vitro RNA structurome of Yersinia pseudotuberculosis

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

Analysis of differentially expressed proteins in Yersinia enterocolitica-infected HeLa cells

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