Bacterial thiol oxidoreductases — from basic research to new antibacterial strategies

Bocian-Ostrzycka, Katarzyna M.; Grzeszczuk, Magdalena; Banaś, Anna Marta; Jagusztyn-Krynicka, Elżbieta Katarzyna

doi:10.1007/s00253-017-8291-8

Cited by 27 publications

(34 citation statements)

References 130 publications

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“…DsbA, one of the most oxidizing proteins known, is a periplasmic thiol-disulfide oxidoreductase of the thioredoxin family with a conserved CXXC domain maintained oxidized in vivo (7,8). After being reduced by oxidizing its substrates, DsbA is then recycled back to the oxidized form by the inner membrane protein DsbB, which generates disulfides de novo from quinone reduction (9). In addition to cyts c, substrates of the DsbA/DsbB system are many, and some of these are essential for pathogens to establish infections and cause disease; as a result, these redox enzymes are attractive targets for pharmacological interventions (10,11).…”

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confidence: 99%

Complex Oxidation of Apocytochromes c during Bacterial Cytochrome c Maturation

Guo

Wang

et al. 2019

Appl Environ Microbiol

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c-Type cytochromes (cyts c) are proteins that contain covalently bound heme and that thus require posttranslational modification for activity, a process carried out by the cytochrome c (cyt c) maturation system (referred to as the Ccm system) in many Gram-negative bacteria. It has been established that during cyt c maturation (CCM), two cysteine thiols of the heme binding motif (CXXCH) within apocytochromes c (apocyts c) are first oxidized largely by DsbA to form a disulfide bond, which is later reduced through a thio-reductive pathway involving DsbD. However, the physiological impacts of DsbA proteins on CCM in fact vary significantly among bacteria. In this work, we used the cyt c-rich Gram-negative bacterium Shewanella oneidensis as the research model to clarify the roles of DsbA proteins in CCM. We show that in terms of the oxidation of apocyts c, DsbA proteins are an important but not critical factor, and, strikingly, oxygen is not either. By exploiting the DsbD-independent pathway, we identify DsbA1, DsbA2, and DsbA3 as oxidants contributing to the oxidation of apocyts c and reductants, such as cysteine, to be an effective antagonist against DsbA-independent oxidation. We further show that DsbB proteins are partially responsible for the reoxidization of reduced DsbA proteins. Overall, our results indicate that the DsbA-DsbB redox pair has a limited role in CCM, challenging the established notion that it is the main oxidant for apocyts c. IMPORTANCE DsbA is a powerful oxidase that functions in the bacterial periplasm to introduce disulfide bonds in many proteins, including apocytochromes c. It has been well established that although DsbA is not essential, it plays a primary role in cytochrome c maturation, based on studies in bacteria hosting several cyts c. Here, with cyt c-rich S. oneidensis as a research model, we show that this is not always the case. Moreover, we demonstrate that DsbB is also not essential for cytochrome c maturation. These results underscore the need to identify oxidants other than DsbA/DsbB that are crucial in the oxidation of apocyts c in bacteria.

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confidence: 99%

Complex Oxidation of Apocytochromes c during Bacterial Cytochrome c Maturation

Guo

Wang

et al. 2019

Appl Environ Microbiol

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“…If they do participate in disulfide bond formation, this would be a unique feature of native YscX, and gives a reason as to why heterologous YscX-like proteins that lack these two conserved cysteines are not functional in Yersinia . It is well-established that disulfide bonds are an important structural element of the secretome of bacterial pathogens (De Geyter et al, 2016 ; Bocian-Ostrzycka et al, 2017 ). This is true also for human pathogenic Yersinia sp., where a role for thiol bonding is reported for the Ysc-Yop T3SS, the Caf1 chaperone-usher system, and the invasin autotransporter (Leong et al, 1993 ; Zav'yalov et al, 1997 ; Jackson and Plano, 1999 ; Mitchell et al, 2017 ).…”

Section: Discussionmentioning

confidence: 99%

Heterologous Complementation Studies With the YscX and YscY Protein Families Reveals a Specificity for Yersinia pseudotuberculosis Type III Secretion

Gurung

Amer

Francis

et al. 2018

Front. Cell. Infect. Microbiol.

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Type III secretion systems harbored by several Gram-negative bacteria are often used to deliver host-modulating effectors into infected eukaryotic cells. About 20 core proteins are needed for assembly of a secretion apparatus. Several of these proteins are genetically and functionally conserved in type III secretion systems of bacteria associated with invertebrate or vertebrate hosts. In the Ysc family of type III secretion systems are two poorly characterized protein families, the YscX family and the YscY family. In the plasmid-encoded Ysc-Yop type III secretion system of human pathogenic Yersinia species, YscX is a secreted substrate while YscY is its non-secreted cognate chaperone. Critically, neither an yscX nor yscY null mutant of Yersinia is capable of type III secretion. In this study, we show that the genetic equivalents of these proteins produced as components of other type III secretion systems of Pseudomonas aeruginosa (PscX and PscY), Aeromonas species (AscX and AscY), Vibrio species (VscX and VscY), and Photorhabdus luminescens (SctX and SctY) all possess an ability to interact with its native cognate partner and also establish cross-reciprocal binding to non-cognate partners as judged by a yeast two-hybrid assay. Moreover, a yeast three-hybrid assay also revealed that these heterodimeric complexes could maintain an interaction with YscV family members, a core membrane component of all type III secretion systems. Despite maintaining these molecular interactions, only expression of the native yscX in the near full-length yscX deletion and native yscY in the near full-length yscY deletion were able to complement for their general substrate secretion defects. Hence, YscX and YscY must have co-evolved to confer an important function specifically critical for Yersinia type III secretion.

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“…Mice infected with B. pseudomallei DsbA knockouts (or of its redox partner DsbB) have an increased rate of survival compared with mice infected with wild type B. pseudomallei [25, 26]. These findings suggest that many B. pseudomallei virulence factors are substrates of DsbA, as is also observed in Escherichia coli [27, 28], Klebsiella pneumoniae [29], Salmonella enterica [30], Francisella tularensis [31] and many more [22, 23, 32]. However, the full extent of B. pseudomallei DsbA substrates has not been investigated.…”

Section: Introductionmentioning

confidence: 93%

“…In bacteria, the introduction of disulfide bonds is mediated by the DiSufide Bond-forming proteins (DSB). The DSB proteins are of particular interest as an antivirulence strategy, because many virulence factors contain disulfide bonds [19, 21-23]. The Disulfide bond forming protein A (DsbA) is a periplasmic protein found in most Gram-negative bacteria and incorporates a thioredoxin fold with two cysteines which introduce disulfide bonds into substrate proteins via a redox transfer reaction [24].…”

Section: Introductionmentioning

confidence: 99%

Prediction ofBurkholderia pseudomalleiDsbA substrates identifies potential virulence factors and vaccine targets

Vezina

Petit

Martin

et al. 2020

Preprint

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AbstractIdentification of bacterial virulence factors is critical for understanding disease pathogenesis, drug discovery and vaccine development. In this study we used two approaches to predict virulence factors of Burkholderia pseudomallei, the Gram-negative bacterium that causes melioidosis. B. pseudomallei is naturally antibiotic resistant and there are no melioidosis vaccines. To identify B. pseudomallei protein targets for drug discovery and vaccine development, we chose to search for substrates of the B. pseudomallei periplasmic disulfide bond forming protein A (DsbA). DsbA introduces disulfide bonds into extra-cytoplasmic proteins and is essential for virulence in many Gram-negative organism, including B. pseudomallei. The first approach to identify B. pseudomallei DsbA virulence factor substrates was a large-scale genomic analysis of 511 unique B. pseudomallei disease-associated strains. This yielded 4,496 core gene products, of which we hypothesise 263 are DsbA substrates. Manual curation of the 263 mature proteins yielded 73 associated with disease pathogenesis or virulence. These were screened for structural homologues to predict potential B-cell epitopes. In the second approach, we searched the B. pseudomallei genome for homologues of the more than 90 known DsbA substrates in other bacteria. Using this approach, we identified 15 potential B. pseudomallei DsbA virulence factor substrates. Two putative B. pseudomallei virulence factors were identified by both methods: homologues of PenI family β-lactamase and of succinate dehydrogenase flavoprotein subunit. These two proteins could serve as high priority targets for future B. pseudomallei virulence factor characterization.

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Bacterial thiol oxidoreductases — from basic research to new antibacterial strategies

Cited by 27 publications

References 130 publications

Complex Oxidation of Apocytochromes c during Bacterial Cytochrome c Maturation

Complex Oxidation of Apocytochromes c during Bacterial Cytochrome c Maturation

Heterologous Complementation Studies With the YscX and YscY Protein Families Reveals a Specificity for Yersinia pseudotuberculosis Type III Secretion

Prediction ofBurkholderia pseudomalleiDsbA substrates identifies potential virulence factors and vaccine targets

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