Pleiotropic clostridioides difficile cyclophilin PpiB controls cysteine-tolerance, toxin production, the central metabolism and multiple stress responses

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dc.contributor.authorÜnal, Can Murat
dc.contributor.authorKaragoz, Mustafa Safa
dc.contributor.authorBerges, Mareike
dc.contributor.authorPriebe, Christina
dc.contributor.authorde Acuna, Jose Manuel Borrero
dc.contributor.authorWissing, Josef
dc.contributor.authorSteinert, Michael
dc.date.accessioned2021-01-08T21:51:22Z
dc.date.available2021-01-08T21:51:22Z
dc.date.issued2019
dc.departmentTAÜ, Fen Fakültesi, Moleküler Biyoteknoloji Bölümüen_US
dc.descriptionde Acuna, Jose Manuel Borrero/0000-0002-6409-8110; Unal, Can/0000-0003-4710-9567; Jansch, Lothar/0000-0002-5655-1181en_US
dc.descriptionWOS:000463536400001en_US
dc.descriptionPubMed: 31024308en_US
dc.description.abstractThe Gram-positive pathogen Clostridioides difficile is the main bacterial agent of nosocomial antibiotic associated diarrhea. Bacterial peptidyl-prolyl-cis/trans-isomerases (PPlases) are well established modulators of virulence that influence the outcome of human pathologies during infections. Here, we present the first interactomic network of the sole cyclophilin-type PPlase of C. difficile (CdPpiB) and show that it has diverse interaction partners including major enzymes of the amino acid-dependent energy (LdhA, EtfAB, Had, Acd) and the glucose-derived (Fba, GapA, Pfo, Pyk, Pyc) central metabolism. Proteins of the general (UspA), oxidative (Rbr1,2,3, Dsr), alkaline (YloU, YphY) and cold shock (CspB) response were found bound to CdPpiB. The transcriptional (Lrp), translational (InfC, RFF) and folding (GroS, DnaK) control proteins were also found attached. For a crucial enzyme of cysteine metabolism, 0-acetylserine sulfhydrylase (CysK), the global transcription regulator Lrp and the flagellar subunit FliC, these interactions were independently confirmed using a bacterial two hybrid system. The active site residues F50, F109, and F110 of CdPpiB were shown to be important for the interaction with the residue P87 of Lrp. CysK activity after heat denaturation was restored by interaction with CdPpiB. In accordance, tolerance toward cell wall stress caused by the exposure to amoxicillin was reduced. In the absence of CdPpiB, C. difficile was more susceptible toward L-cysteine. At the same time, the cysteinemediated suppression of toxin production ceased resulting in higher cytotoxicity. In summary, the cyclophilin-type PPlase of C. difficile (CdPpiB) coordinates major cellular processes via its interaction with major regulators of transcription, translation, protein folding, stress response and the central metabolism.
dc.description.sponsorshipFederal State of Lower Saxony; Niedersachsisches Vorab CDiff and CDInfect projects [VWZN2889/3215/3266]; German Research FoundationGerman Research Foundation (DFG); Open Access Publication Funds of the Technische Universitat Braunschweig
dc.description.sponsorshipThis work was funded by the Federal State of Lower Saxony, Niedersachsisches Vorab CDiff and CDInfect projects (VWZN2889/3215/3266) as well as by the German Research Foundation and the Open Access Publication Funds of the Technische Universitat Braunschweig.
dc.identifier.doi10.3389/fphar.2019.00340
dc.identifier.issn1663-9812
dc.identifier.scopus2-s2.0-85068459467
dc.identifier.scopusqualityQ1
dc.identifier.urihttp://doi.org/10.3389/fphar.2019.00340
dc.identifier.urihttps://hdl.handle.net/20.500.12846/194
dc.identifier.volume10en_US
dc.identifier.wosWOS:000463536400001
dc.identifier.wosqualityQ1
dc.indekslendigikaynakWeb of Science
dc.indekslendigikaynakScopus
dc.indekslendigikaynakPubMed
dc.institutionauthorÜnal, Can Murat
dc.language.isoen
dc.publisherFrontiers Media Sa
dc.relation.ispartofFrontiers In Pharmacology
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanı
dc.rightsinfo:eu-repo/semantics/openAccess
dc.subjectClostridium Difficileen_US
dc.subjectPeptidyl-Prolyl-Cis/Trans-Isomerase (Pplase)en_US
dc.subjectCytotoxicityen_US
dc.subjectInteractomicsen_US
dc.subjectTranscriptionen_US
dc.titlePleiotropic clostridioides difficile cyclophilin PpiB controls cysteine-tolerance, toxin production, the central metabolism and multiple stress responses
dc.typeArticle

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