Articles producció científica> Ciències Mèdiques Bàsiques

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

  • Datos identificativos

    Identificador: imarina:5130168
    Handle: http://hdl.handle.net/20.500.11797/imarina5130168
  • Autores:

    Gsaller F
    Hortschansky P
    Furukawa T
    Carr PD
    Rash B
    Capilla J
    Müller C
    Bracher F
    Bowyer P
    Haas H
    Brakhage AA
    Bromley MJ
  • Otros:

    Autor según el artículo: Gsaller F; Hortschansky P; Furukawa T; Carr PD; Rash B; Capilla J; Müller C; Bracher F; Bowyer P; Haas H; Brakhage AA; Bromley MJ
    Departamento: Ciències Mèdiques Bàsiques
    Autor/es de la URV: Capilla Luque, Javier
    Palabras clave: Pyrrole derivative Cell extract Ccaat binding factor
    Resumen: 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.
    Áreas temáticas: 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
    Acceso a la licencia de uso: https://creativecommons.org/licenses/by/3.0/es/
    ISSN: 15537366
    Direcció de correo del autor: javier.capilla@urv.cat
    Identificador del autor: 0000-0002-0765-6403
    Fecha de alta del registro: 2023-02-18
    Versión del articulo depositado: info:eu-repo/semantics/publishedVersion
    Enlace a la fuente original: https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1005775
    URL Documento de licencia: http://repositori.urv.cat/ca/proteccio-de-dades/
    Referencia al articulo segun fuente origial: Plos Pathogens. 12 (7): e1005775-
    Referencia de l'ítem segons les normes 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
    DOI del artículo: 27438727
    Entidad: Universitat Rovira i Virgili
    Año de publicación de la revista: 2016
    Tipo de publicación: Journal Publications
  • Palabras clave:

    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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