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: imarina:5130168
    Authors:
    Gsaller FHortschansky PFurukawa TCarr PDRash BCapilla JMüller CBracher FBowyer PHaas HBrakhage AABromley MJ
    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.: Gsaller F; Hortschansky P; Furukawa T; Carr PD; Rash B; Capilla J; Müller C; Bracher F; Bowyer P; Haas H; Brakhage AA; Bromley MJ
    Department: Ciències Mèdiques Bàsiques
    URV's Author/s: Capilla Luque, Javier
    Keywords: Pyrrole derivative Cell extract 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.
    Thematic Areas: Virology Parasitology Molecular biology Microbiology Medicina veterinaria Medicina iii Medicina ii Medicina i Materiais Interdisciplinar Immunology Genetics Farmacia Engenharias iii Enfermagem Ciências biológicas iii Ciências biológicas ii Ciências biológicas i Ciências agrárias i Ciência da computação Biotecnología Biodiversidade
    licence for use: https://creativecommons.org/licenses/by/3.0/es/
    ISSN: 15537366
    Author's mail: javier.capilla@urv.cat
    Author identifier: 0000-0002-0765-6403
    Record's date: 2024-09-07
    Papper version: info:eu-repo/semantics/publishedVersion
    Link to the original source: https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1005775
    Licence document URL: https://repositori.urv.cat/ca/proteccio-de-dades/
    Papper original source: Plos Pathogens. 12 (7): e1005775-
    APA: Gsaller F; Hortschansky P; Furukawa T; Carr PD; Rash B; Capilla J; Müller C; Bracher F; Bowyer P; Haas H; Brakhage AA; Bromley MJ (2016). Sterol Biosynthesis and Azole Tolerance Is Governed by the Opposing Actions of SrbA and the CCAAT Binding Complex. Plos Pathogens, 12(7), e1005775-. DOI: 10.1371/journal.ppat.1005775
    Article's DOI: 10.1371/journal.ppat.1005775
    Entity: Universitat Rovira i Virgili
    Journal publication year: 2016
    Publication Type: Journal Publications
  • Keywords:

    Genetics,Immunology,Microbiology,Molecular Biology,Parasitology,Virology
    Pyrrole derivative
    Cell extract
    Ccaat binding factor
    Virology
    Parasitology
    Molecular biology
    Microbiology
    Medicina veterinaria
    Medicina iii
    Medicina ii
    Medicina i
    Materiais
    Interdisciplinar
    Immunology
    Genetics
    Farmacia
    Engenharias iii
    Enfermagem
    Ciências biológicas iii
    Ciências biológicas ii
    Ciências biológicas i
    Ciências agrárias i
    Ciência da computação
    Biotecnología
    Biodiversidade
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