Articles producció científica> Ciències Mèdiques Bàsiques

Sterol Biosynthesis and Azole Tolerance Is Governed by the Opposing Actions of SrbA and the CCAAT Binding Complex

  • Identification data

    Identifier: PC:1834
    Handle: https://hdl.handle.net/20.500.11797/PC1834
    Authors:
    Javier CapillaFabio GsallerPeter HortschanskyTakanori FurukawaPaul D. CarrBharat RashChristoph MüllerFranz BracherPaul BowyerHubertus HaasAxel A. BrakhageMichael J. Bromley
    Abstract:
    Azole drugs selectively target fungal sterol biosynthesis and are critical to our antifungal therapeutic arsenal. However, resistance to this class of drugs, particularly in the major human mould pathogen Aspergillus fumigatus, is emerging and reaching levels that have prompted some to suggest that there is a realistic probability that they will be lost for clinical use. The dominating class of pan-azole resistant isolates is characterized by the presence of a tandem repeat of at least 34 bases (TR34) within the promoter of cyp51A, the gene encoding the azole drug target sterol C14-demethylase. Here we demonstrate that the repeat sequence in TR34 is bound by both the sterol regulatory element binding protein (SREBP) SrbA, and the CCAAT binding complex (CBC). We show that the CBC acts complementary to SrbA as a negative regulator of ergosterol biosynthesis and show that lack of CBC activity results in increased sterol levels via transcriptional derepression of multiple ergosterol biosynthetic genes including those coding for HMG-CoA-synthase, HMG-CoA-reductase and sterol C14-demethylase. In agreement with these findings, inactivation of the CBC increased tolerance to different classes of drugs targeting ergosterol biosynthesis including the azoles, allylamines (terbinafine) and statins (simvastatin). We reveal that a clinically relevant mutation in HapE (P88L) significantly impairs the binding affinity of the CBC to its target site. We identify that the mechanism underpinning TR34 driven overexpression of cyp51A results from duplication of SrbA but not CBC binding sites and show that deletion of the 34 mer results in lack of cyp51A expression and increased azole susceptibility similar to a cyp51A null mutant. Finally we show that strains lacking a functional CBC are seve

  • Others:

    Author, as appears in the article.: Javier Capilla; Fabio Gsaller; Peter Hortschansky; Takanori Furukawa; Paul D. Carr; Bharat Rash; Christoph Müller; Franz Bracher; Paul Bowyer; Hubertus Haas; Axel A. Brakhage; Michael J. Bromley
    Department: Ciències Mèdiques Bàsiques
    URV's Author/s: CAPILLA LUQUE, JAVIER
    Keywords: cell extract pyrrole derivative CCAAT binding factor
    Abstract: Azole drugs selectively target fungal sterol biosynthesis and are critical to our antifungal therapeutic arsenal. However, resistance to this class of drugs, particularly in the major human mould pathogen Aspergillus fumigatus, is emerging and reaching levels that have prompted some to suggest that there is a realistic probability that they will be lost for clinical use. The dominating class of pan-azole resistant isolates is characterized by the presence of a tandem repeat of at least 34 bases (TR34) within the promoter of cyp51A, the gene encoding the azole drug target sterol C14-demethylase. Here we demonstrate that the repeat sequence in TR34 is bound by both the sterol regulatory element binding protein (SREBP) SrbA, and the CCAAT binding complex (CBC). We show that the CBC acts complementary to SrbA as a negative regulator of ergosterol biosynthesis and show that lack of CBC activity results in increased sterol levels via transcriptional derepression of multiple ergosterol biosynthetic genes including those coding for HMG-CoA-synthase, HMG-CoA-reductase and sterol C14-demethylase. In agreement with these findings, inactivation of the CBC increased tolerance to different classes of drugs targeting ergosterol biosynthesis including the azoles, allylamines (terbinafine) and statins (simvastatin). We reveal that a clinically relevant mutation in HapE (P88L) significantly impairs the binding affinity of the CBC to its target site. We identify that the mechanism underpinning TR34 driven overexpression of cyp51A results from duplication of SrbA but not CBC binding sites and show that deletion of the 34 mer results in lack of cyp51A expression and increased azole susceptibility similar to a cyp51A null mutant. Finally we show that strains lacking a functional CBC are severely attenuated for pathogenicity in a pulmonary and systemic model of aspergillosis.
    Research group: Unitat de Micologia i Microbiologia Ambiental
    Thematic Areas: Health sciences Ciencias de la salud Ciències de la salut
    licence for use: https://creativecommons.org/licenses/by/3.0/es/
    ISSN: 1553-7366
    Author identifier: N/D; N/D; N/D; N/D; N/D; N/D; N/D; N/D; N/D; N/D; N/D; N/D
    Record's date: 2016-09-20
    Last page: 22p
    Journal volume: 12
    Papper version: info:eu-repo/semantics/publishedVersion
    Licence document URL: https://repositori.urv.cat/ca/proteccio-de-dades/
    Entity: Universitat Rovira i Virgili
    Journal publication year: 2016
    First page: Art.num. e1005775
    Publication Type: Article Artículo Article

  • Keywords:

    Fongs patògens
    Micologia mèdica
    cell extract
    pyrrole derivative
    CCAAT binding factor
    Health sciences
    Ciencias de la salud
    Ciències de la salut
    1553-7366

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