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

Joshi, Avatar; Mahmoud, Samar A.; Kim, Sang-Yong; Ogdahl, Justyne L.; Lee, Vincent T.; Yildiz, Fitnat H.

doi:10.1371/journal.pgen.1008897

Cited by 22 publications

(15 citation statements)

References 51 publications

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“…But, the mechanisms or external signals that induce the secretion activity is not fully known. LonA belongs to the superfamily of ATPases that repress the T6SS and influence T6SS-dependent killing phenotypes differently in V. cholerae strains with high and low levels of c-d-GMP (Joshi et al, 2020 ).…”

Section: Regulation Of Secretion Systems (T2ss/t3ss/t6ss)mentioning

confidence: 99%

Virulence Regulation and Innate Host Response in the Pathogenicity of Vibrio cholerae

Ramamurthy

Nandy

Mukhopadhyay

et al. 2020

Front. Cell. Infect. Microbiol.

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The human pathogen Vibrio cholerae is the causative agent of severe diarrheal disease known as cholera. Of the more than 200 "O" serogroups of this pathogen, O1 and O139 cause cholera outbreaks and epidemics. The rest of the serogroups, collectively known as non-O1/non-O139 cause sporadic moderate or mild diarrhea and also systemic infections. Pathogenic V. cholerae circulates between nutrient-rich human gut and nutrient-deprived aquatic environment. As an autochthonous bacterium in the environment and as a human pathogen, V. cholerae maintains its survival and proliferation in these two niches. Growth in the gastrointestinal tract involves expression of several genes that provide bacterial resistance against host factors. An intricate regulatory program involving extracellular signaling inputs is also controlling this function. On the other hand, the ability to store carbon as glycogen facilitates bacterial fitness in the aquatic environment. To initiate the infection, V. cholerae must colonize the small intestine after successfully passing through the acid barrier in the stomach and survive in the presence of bile and antimicrobial peptides in the intestinal lumen and mucus, respectively. In V. cholerae, virulence is a multilocus phenomenon with a large functionally associated network. More than 200 proteins have been identified that are functionally linked to the virulence-associated genes of the pathogen. Several of these genes have a role to play in virulence and/or in functions that have importance in the human host or the environment. A total of 524 genes are differentially expressed in classical and El Tor strains, the two biotypes of V. cholerae serogroup O1. Within the host, many immune and biological factors are able to induce genes that are responsible for survival, colonization, and virulence. The innate host immune response to V. cholerae infection includes activation of several immune protein complexes, receptor-mediated signaling pathways, and other bactericidal proteins. This article presents an overview of regulation of important virulence factors in V. cholerae and host response in the context of pathogenesis.

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Section: Regulation Of Secretion Systems (T2ss/t3ss/t6ss)mentioning

confidence: 99%

Virulence Regulation and Innate Host Response in the Pathogenicity of Vibrio cholerae

Ramamurthy

Nandy

Mukhopadhyay

et al. 2020

Front. Cell. Infect. Microbiol.

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“…Studies of human-derived strains identify two primary TFs for T6 activation (19)(20)(21)(22)(23). T6 control in pandemic strains (e.g.…”

Section: Introductionmentioning

confidence: 99%

“…C6706) requires QstR (Quorum-Sensing and TfoX-Dependent Regulator), which integrates multiple external cues (24)(25)(26)(27), and contains a DNA binding domain postulated to interact with a presumptive CRE of the major T6 gene cluster (20,24). T6 regulation in non-pandemic strain V52, which causes mild disease, requires TfoY, modulatable by intracellular signals (22,23). How QstR and TfoY control T6 transcription remains elusive, with no T6 CRE yet described.…”

Section: Introductionmentioning

confidence: 99%

Evolution of a cis-acting SNP that controls Type VI Secretion in Vibrio cholerae

Kammann

Steinbach

et al. 2022

Preprint

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Mutations in regulatory mechanisms that control gene expression contribute to phenotypic diversity and thus facilitate the adaptation of microbes to new niches. Regulatory architecture is often inferred from transcription factor identification and genome analysis using purely computational approaches. However, there are few examples of phenotypic divergence that arise from the rewiring of bacterial regulatory circuity by mutations in intergenic regions, because locating regulatory elements within regions of DNA that do not code for protein requires genomic and experimental data. We identify a single cis-acting single nucleotide polymorphism (SNP) dramatically alters control of the type VI secretion system (T6), a common weapon for inter-bacterial competition. Tight T6 regulatory control is necessary for adaptation of the waterborne pathogen Vibrio cholerae to in vivo conditions within the human gut, which we show can be altered by this single non-coding SNP that results in constitutive expression in vitro. Our results support a model of pathogen evolution through cis-regulatory mutation and preexisting, active transcription factors, thus conferring different fitness advantages to tightly regulated strains inside a human host and unfettered strains adapted to environmental niches.

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“…Most knowledge about Lon has been obtained by studying bacterial Lon orthologs. In Escherichia coli , Lon specifically degrades several stress-induced regulators ( Griffith et al, 2004 ; Langklotz and Narberhaus, 2011 ; Mizusawa and Gottesman, 1983 ), metabolic enzymes ( Arends et al, 2018 ) as well as antitoxins of toxin-antitoxin systems ( Muthuramalingam et al, 2016 ), and in several pathogenic bacteria, Lon was shown to degrade regulators of pathogenicity ( Joshi et al, 2020 ; Puri and Karzai, 2017 ), thus playing important roles in the regulation of virulence pathways. In the alpha-proteobacterium Caulobacter crescentus , the number of identified Lon substrates to date is small, however, Lon is known to impact cell cycle progression by degrading essential cell cycle regulators.…”

Section: Introductionmentioning

confidence: 99%

The Lon protease temporally restricts polar cell differentiation events during the Caulobacter cell cycle

Omnus

Fink

Szwedo

et al. 2021

eLife

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The highly conserved protease Lon has important regulatory and protein quality control functions in cells from the three domains of life. Despite many years of research on Lon, only a few specific protein substrates are known in most organisms. Here, we used a quantitative proteomics approach to identify novel substrates of Lon in the dimorphic bacterium Caulobacter crescentus. We focused our study on proteins involved in polar cell differentiation and investigated the developmental regulator StaR and the flagella hook length regulator FliK as specific Lon substrates in detail. We show that Lon recognizes these proteins at their C-termini, and that Lon-dependent degradation ensures their temporally restricted accumulation in the cell cycle phase when their function is needed. Disruption of this precise temporal regulation of StaR and FliK levels in a Δlon mutant contributes to defects in stalk biogenesis and motility, respectively, revealing a critical role of Lon in coordinating developmental processes with cell cycle progression. Our work underscores the importance of Lon in the regulation of complex temporally controlled processes by adjusting the concentrations of critical regulatory proteins. Furthermore, this study includes the first characterization of FliK in C. crescentus and uncovers a dual role of the C-terminal amino acids of FliK in protein function and degradation.

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

Cited by 22 publications

References 51 publications

Virulence Regulation and Innate Host Response in the Pathogenicity of Vibrio cholerae

Virulence Regulation and Innate Host Response in the Pathogenicity of Vibrio cholerae

Evolution of a cis-acting SNP that controls Type VI Secretion in Vibrio cholerae

The Lon protease temporally restricts polar cell differentiation events during the Caulobacter cell cycle

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