AAA+ proteases and their role in distinct stages along the Vibrio cholerae lifecycle

Preßler, Katharina; Vorkapić, Dina; Lichtenegger, Sabine; Malli, Gerald; Barilich, Benjamin P.; Çakar, Fatih; Zingl, Franz G.; Reidl, Joachim; Schild, Stefan

doi:10.1016/j.ijmm.2016.05.013

Cited by 12 publications

(17 citation statements)

References 97 publications

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“…Based on the current model, flagellar motility is activated upon entrance in the human host to allow proper attachment and penetration through the mucosal layer. After the initial stage of infection and in agreement with our results, down-regulation of flagellar synthesis is essential to relieve the repression on virulence factors and enhance colonization fitness ( 31 , 32 ). In contrast, bacteria initiate an RpoS-dependent mucosal escape response at later stages, where the bacteria up-regulate chemotaxis and motility genes, detach from the epithelial surface into the fluid-filled lumen, and eventually exit the host ( 5 , 33 ).…”

Section: Resultssupporting

confidence: 90%

In vivo repressed genes of Vibrio cholerae reveal inverse requirements of an H ⁺ /Cl ⁻ transporter along the gastrointestinal passage

Çakar

Zingl

Moisi

et al. 2018

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

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SignificanceBacterial infection is still a global threat to human health. Gene expression profiling of pathogenic bacteria during infection may aid in a better understanding of the pathophysiological events. Here, we present a reporter-based technology to identify in vivo repressed (ivr) genes of Vibrio cholerae. Our data demonstrate that constitutive expression of ivr genes reduces colonization fitness, indicating a pivotal role of gene silencing. A comprehensive characterization of an H+/Cl− transporter revealed a defined spatiotemporal expression pattern, being induced in the stomach to facilitate survival under low pH, but silenced under alkaline pH in the lower gastrointestinal tract to avoid detrimental effects. Thus, previously understudied ivr genes could reveal new insights into host–pathogen interaction and alternative therapeutic strategies.

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Section: Resultssupporting

confidence: 90%

In vivo repressed genes of Vibrio cholerae reveal inverse requirements of an H ⁺ /Cl ⁻ transporter along the gastrointestinal passage

Çakar

Zingl

Moisi

et al. 2018

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

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“…Prior to this study only two LonA substrates had been identified in V. cholerae [8,23]. The first is the alternative sigma factor FliA, which helps coordinate the activation of late stage flagellar genes and also acts to repress virulence factor production [8,31].…”

Section: Discussionmentioning

confidence: 99%

“…For example, in many bacterial species, loss of lonA results in aberrant cell division, susceptibility to stressors such as UV irradiation and heat shock, as well as aberrant control of motility, biofilm formation, quorum sensing, virulence factor production, and host colonization. Indeed, deletion of lonA significantly reduces the in vivo fitness of every pathogenic bacteria in which it has been tested [4][5][6][7][8][9][10][11][12].…”

Section: Introductionmentioning

confidence: 99%

“…To date, only two known LonA substrates have been identified in V. cholerae. The first is FliA, an alternative sigma factor (σ 28 ) that coordinates the activation of late stage flagellar genes and the repression of virulence gene expression [8]. The second is the quorum sensing master regulator HapR, which is proteolyzed by LonA upon heat shock in order to induce biofilm formation [23].…”

Section: Introductionmentioning

confidence: 99%

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c-di-GMP inhibits LonA-dependent proteolysis of TfoY in Vibrio cholerae

et al. 2020

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The LonA (or Lon) protease is a central post-translational regulator in diverse bacterial species. In Vibrio cholerae, LonA regulates a broad range of behaviors including cell division, biofilm formation, flagellar motility, c-di-GMP levels, the type VI secretion system (T6SS), virulence gene expression, and host colonization. Despite LonA's role in cellular processes critical for V. cholerae's aquatic and infectious life cycles, relatively few LonA substrates have been identified. LonA protease substrates were therefore identified through comparison of the proteomes of wild-type and ΔlonA strains following translational inhibition. The most significantly enriched LonA-dependent protein was TfoY, a known regulator of motility and the T6SS in V. cholerae. Experiments showed that TfoY was required for LonA-mediated repression of motility and T6SS-dependent killing. In addition, TfoY was stabilized under high c-di-GMP conditions and biochemical analysis determined direct binding of c-di-GMP to LonA results in inhibition of its protease activity. The work presented here adds to the list of LonA substrates, identifies LonA as a c-di-GMP receptor, demonstrates that c-di-GMP regulates LonA activity and TfoY protein stability, and helps elucidate the mechanisms by which LonA controls important V. cholerae behaviors.

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“…26,27 Once V. cholerae has digged into the mucus, flagellar motility becomes dispensable and flagellar gene expression is tuned down by a Lon-dependent proteolysis of FliA to allow full virulence gene expression. [28][29][30] At the late stage of infection V. cholerae activates a RpoSdependent mucosal escape response to again induce flagella and chemotaxis genes, which facilitates detachment from the epithelium and transition into the aquatic environment. 8,31 Our data suggests that constitutive expression of FlrA can be as detrimental for colonization fitness as presence of FliA, which is a potent inhibitor for virulence gene expression.…”

Section: Reduced Colonization Fitness Of Strain Overexpressing Ivr Gementioning

confidence: 99%

Silence is golden: gene silencing of V. cholerae during intestinal colonization delivers new aspects to the acid tolerance response

2018

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Bacterial pathogens of the gastrointestinal tract alter their expression profile upon ingestion by the host and activate a variety of factors enhancing colonization and virulence. However, gene silencing during infection might be as important as gene activation to achieve full colonization fitness. Thus, we developed and successfully applied a reporter technology to identify 101 in vivo repressed (ivr) genes of the bacterial pathogen Vibrio cholerae. In depth analysis of the in vivo repressed H/Cl transporter ClcA revealed an inverse requirement along gastrointestinal colonization. ClcA could be linked to acid tolerance response required during stomach passage, but ClcA expression is detrimental during subsequent colonization of the lower intestinal tract as it exploits the proton-motive force in alkaline environments. The study summarized in this addendum demonstrates that constitutive expression of ivr genes can reduce intestinal colonization fitness of V. cholerae, highlighting the necessity to downregulate these genes in vivo.

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AAA+ proteases and their role in distinct stages along the Vibrio cholerae lifecycle

Cited by 12 publications

References 97 publications

In vivo repressed genes of Vibrio cholerae reveal inverse requirements of an H ⁺ /Cl ⁻ transporter along the gastrointestinal passage

In vivo repressed genes of Vibrio cholerae reveal inverse requirements of an H ⁺ /Cl ⁻ transporter along the gastrointestinal passage

c-di-GMP inhibits LonA-dependent proteolysis of TfoY in Vibrio cholerae

Silence is golden: gene silencing of V. cholerae during intestinal colonization delivers new aspects to the acid tolerance response

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AAA+ proteases and their role in distinct stages along the Vibrio cholerae lifecycle

Cited by 12 publications

References 97 publications

In vivo repressed genes of Vibrio cholerae reveal inverse requirements of an H + /Cl − transporter along the gastrointestinal passage

In vivo repressed genes of Vibrio cholerae reveal inverse requirements of an H + /Cl − transporter along the gastrointestinal passage

c-di-GMP inhibits LonA-dependent proteolysis of TfoY in Vibrio cholerae

Silence is golden: gene silencing of V. cholerae during intestinal colonization delivers new aspects to the acid tolerance response

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In vivo repressed genes of Vibrio cholerae reveal inverse requirements of an H ⁺ /Cl ⁻ transporter along the gastrointestinal passage

In vivo repressed genes of Vibrio cholerae reveal inverse requirements of an H ⁺ /Cl ⁻ transporter along the gastrointestinal passage