A bacterial secreted translocator hijacks riboregulators to control type III secretion in response to host cell contact

Kusmierek, Maria; Hoßmann, Jörn; Witte, Rebekka; Opitz, Wiebke; Vollmer, Ines; Volk, Marcel; Heroven, Ann Kathrin; Wolf‐Watz, Hans; Dersch, Petra

doi:10.1371/journal.ppat.1007813

Cited by 26 publications

(59 citation statements)

References 79 publications

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“…Therefore, it is possible that some of the YopE detected in the supernatant of the Apo-IscR strain is a result of lysis rather than type III secretion. However, the 5-fold greater YopE levels in the cell pellet of the Apo-IscR mutant compared to WT (Fig 6) corroborates the hypothesis that this mutant is undergoing type III secretion, as active secretion feeds back on T3SS gene transcript levels through a positive feedback loop [31]. These results demonstrate that increasing IscR levels is sufficient to activate T3SS expression under anaerobic conditions.…”

Section: Ectopic Induction Of Iscr Under Anaerobic Conditions Is Suffsupporting

confidence: 73%

“…While T3SS gene expression was detected within the entire splenic microcolony, enhanced expression was detected in bacteria localized at the microcolony periphery, i.e.-those bacteria in contact with host cells. It is possible that this T3SS expression in the microcolony periphery reflects host cell contact-dependent increase in type III secretion, leading to stabilization of lcrF and other T3SS genes [31]. This contact-dependent increase in T3SS gene expression is then an additional layer of regulation once IscR levels are high enough in deeper tissues to induce sufficient lcrF mRNA production.…”

Section: Discussionmentioning

confidence: 99%

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Iron availability and oxygen tension regulate the Yersinia Ysc type III secretion system to enable disseminated infection

et al. 2019

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The enteropathogen Yersinia pseudotuberculosis and the related plague agent Y. pestis require the Ysc type III secretion system (T3SS) to subvert phagocyte defense mechanisms and cause disease. Yet type III secretion (T3S) in Yersinia induces growth arrest and innate immune recognition, necessitating tight regulation of the T3SS. Here we show that Y. pseudotuberculosis T3SS expression is kept low under anaerobic, iron-rich conditions, such as those found in the intestinal lumen where the Yersinia T3SS is not required for growth. In contrast, the Yersinia T3SS is expressed under aerobic or anaerobic, iron-poor conditions, such as those encountered by Yersinia once they cross the epithelial barrier and encounter phagocytic cells. We further show that the [2Fe-2S] containing transcription factor, IscR, mediates this oxygen and iron regulation of the T3SS by controlling transcription of the T3SS master regulator LcrF. IscR binds directly to the lcrF promoter and, importantly, a mutation that prevents this binding leads to decreased disseminated infection of Y. pseudotuberculosis but does not perturb intestinal colonization. Similar to E. coli, Y. pseudotuberculosis uses the Fe-S cluster occupancy of IscR as a readout of oxygen and iron conditions that impact cellular Fe-S cluster homeostasis. We propose that Y. pseudotuberculosis has coopted this system to sense entry into deeper tissues and induce T3S where it is required for virulence. The IscR binding site in the lcrF promoter is completely conserved between Y. pseudotuberculosis and Y. pestis. Deletion of iscR in Y. pestis leads to drastic disruption of T3S, suggesting that IscR control of the T3SS evolved before Y. pestis split from Y. pseudotuberculosis. Author summaryThe Yersinia type III secretion system (T3SS) is an important virulence factor of the enteropathogen Yersinia pseudotuberculosis as well as Yersinia pestis, the causative agent of PLOS Pathogens | https://doi.

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Section: Ectopic Induction Of Iscr Under Anaerobic Conditions Is Suffsupporting

confidence: 73%

Section: Discussionmentioning

confidence: 99%

Iron availability and oxygen tension regulate the Yersinia Ysc type III secretion system to enable disseminated infection

et al. 2019

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“…Therefore, VirD2 may have enzymatic functions both within the bacterium and in the host plant cell. A recent study also indicated that Yersinia pseudotuberculosis uses the secreted T3SS translocator YopD to control RNA regulators and increase the abundance of LcrF, a common transcriptional activator of other T3SS effector genes 12 . N-linked protein glycosylation on arginine has also been reported for the EarP glycosyltransferase from E. coli and Pseudomonas aeruginosa 13 .…”

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confidence: 99%

An intra-bacterial activity for a T3SS effector

Qaidi

Scott

Hays

et al. 2020

Sci Rep

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Many Gram-negative bacterial pathogens interact with mammalian cells by using type iii secretion systems (T3SS) to inject virulence proteins into host cells. A subset of these injected protein 'effectors' are enzymes that inhibit the function of host proteins by catalyzing the addition of unusual posttranslational modifications. The E. coli and Citrobacter rodentium NleB effectors, as well as the Salmonella enterica SseK effectors are glycosyltransferases that modify host protein substrates with N-acetyl glucosamine (GlcNAc) on arginine residues. This post-translational modification disrupts the normal functioning of host immune response proteins. T3SS effectors are thought to be inactive within the bacterium and fold into their active conformations after they are injected, due to the activity of chaperones that keep the effectors in a structural state permissive for secretion. While performing mass spectrometry experiments to identify glycosylation substrates of nleB orthologs, we unexpectedly observed that the bacterial glutathione synthetase (GshB) is glycosylated by NleB on arginine residue R256. NleB-mediated glycosylation of GshB resulted in enhanced GshB activity, leading to an increase in glutathione production, and promoted C. rodentium survival in oxidative stress conditions. these data represent, to our knowledge, the first intra-bacterial activity for a T3SS effector and show that arginine-GlcnAcylation, once thought to be restricted to host cell compartments, also plays an important role in regulating bacterial physiology.

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“…Moreover, a consistently high degree of correlation between yscWp promoter activity and levels of secreted Yops was observed (Figs 4 and 5). This is impressive considering the complexity of transcriptional and post-transcriptional control of the yscWp transcriptional unit [51][52][53]. This represents compelling evidence for CpxR/RscB regulatory interplay in Ysc-Yop T3SS control, despite indications that active CpxR~P may not directly bind to rscB regulatory region ( Figs S3 and S4).…”

Section: Zinc-activated Rcsb Expression Is Subdued By Active Cpxrmentioning

confidence: 87%

CpxR regulates the Rcs phosphorelay system in controlling the Ysc-Yop type III secretion system in Yersinia pseudotuberculosis

Fei

Chao

et al. 2021

Microbiology

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The CpxRA two-component regulatory system and the Rcs phosphorelay system are both employed by the Enterobacteriaceae family to preserve bacterial envelope integrity and function when growing under stress. Although both systems regulate several overlapping physiological processes, evidence demonstrating a molecular connection between Cpx and Rcs signalling outputs is scarce. Here, we show that CpxR negatively regulates the transcription of the rcsB gene in the Rcs phosphorelay system in Yersinia pseudotuberculosis . Interestingly, transcription of rcsB is under the control of three promoters, which were all repressed by CpxR. Critically, synthetic activation of Cpx signalling through mislocalization of the NlpE lipoprotein to the inner membrane resulted in an active form of CpxR that repressed activity of rcsB promoters. On the other hand, a site-directed mutation of the phosphorylation site at residue 51 in CpxR generated an inactive non-phosphorylated variant that was unable to regulate output from these rcsB promoters. Importantly, CpxR-mediated inhibition of rcsB transcription in turn restricted activation of the Ysc-Yop type III secretion system (T3SS). Moreover, active CpxR blocks zinc-mediated activation of Rcs signalling and the subsequent activation of lcrF transcription. Our results demonstrate a novel regulatory cascade linking CpxR-RcsB-LcrF to control production of the Ysc-Yop T3SS.

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A bacterial secreted translocator hijacks riboregulators to control type III secretion in response to host cell contact

Cited by 26 publications

References 79 publications

Iron availability and oxygen tension regulate the Yersinia Ysc type III secretion system to enable disseminated infection

Iron availability and oxygen tension regulate the Yersinia Ysc type III secretion system to enable disseminated infection

An intra-bacterial activity for a T3SS effector

CpxR regulates the Rcs phosphorelay system in controlling the Ysc-Yop type III secretion system in Yersinia pseudotuberculosis

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