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Role of long-chain acyl-CoAs in the regulation of mycolic acid biosynthesis in mycobacteria

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dc.citation.titleOpen Biologyes
dc.citation.volume7(7)es
dc.creatorTsai, Yi-Ting
dc.creatorSalzman, Valentina
dc.creatorCabruja, Matías Ezequiel
dc.creatorGago, Gabriela
dc.creatorGramajo, Hugo Cesar
dc.date.accessioned2020-12-22T15:53:50Z
dc.date.available2020-12-22T15:53:50Z
dc.date.issued2017-07-19
dc.descriptionOne of the dominant features of the biology of Mycobacterium tuberculosis, and other mycobacteria, is the mycobacterial cell envelope with its exceptional complex composition. Mycolic acids are major and very specific components of the cell envelope and play a key role in its architecture and impermeability. Biosynthesis of mycolic acid (MA) precursors requires two types of fatty acid synthases, FAS I and FAS II, which should work in concert in order to keep lipid homeostasis tightly regulated. Both FAS systems are regulated at their transcriptional level by specific regulatory proteins. FasR regulates components of the FAS I system, whereas MabR and FadR regulate components of the FAS II system. In this article, by constructing a tight mabR conditional mutant in Mycobacterium smegmatis mc2 155, we demonstrated that sub-physiological levels of MabR lead to a downregulation of the fasII genes, inferring that this protein is a transcriptional activator of the FAS II system. In vivo labelling experiments and lipidomic studies carried out in the wild-type and the mabR conditional mutant demonstrated that under conditions of reduced levels of MabR, there is a clear inhibition of biosynthesis of MAs, with a concomitant change in their relative composition, and of other MA-containing molecules. These studies also demonstrated a change in the phospholipid composition of the membrane of the mutant strain, with a significant increase of phosphatidylinositol. Gel shift assays carried out with MabR and PfasII as a probe in the presence of different chain-length acyl-CoAs strongly suggest that molecules longer than C18 can be sensed by MabR to modulate its affinity for the operator sequences that it recognizes, and in that way switch on or off the MabR-dependent promoter. Finally, we demonstrated the direct role of MabR in the upregulation of the fasII operon genes after isoniazid treatment.es
dc.description.filFil: Tsai, Yi-Ting. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario (IBR -CONICET). Laboratorio de Fisiología y Genética de Actinomycetes; Argentina.es
dc.description.filFil: Salzman, Valentina. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario (IBR -CONICET). Laboratorio de Fisiología y Genética de Actinomycetes; Argentina.es
dc.description.filFil: Cabruja, Matías Ezequiel. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario (IBR -CONICET). Laboratorio de Fisiología y Genética de Actinomycetes; Argentina.es
dc.description.filFil: Gago, Gabriela. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario (IBR -CONICET). Laboratorio de Fisiología y Genética de Actinomycetes; Argentina.es
dc.description.filFil: Gramajo, Hugo Cesar. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario (IBR -CONICET). Laboratorio de Fisiología y Genética de Actinomycetes; Argentina.es
dc.description.sponsorshipAgencia Nacional de Promoción Científica y Tecnológica (ANPCyT): PICT 2011-0245, PICT 2012-0168, PICT 2015-0796 y 2022es
dc.description.sponsorshipNational Institutes of Health (NIH): 1R01AI095183-01es
dc.formatapplication/pdf
dc.format.extent1-15es
dc.identifier.issn2046-2441es
dc.identifier.urihttp://hdl.handle.net/2133/19534
dc.language.isoenges
dc.publisherRoyal Societyes
dc.relation.publisherversionhttps://doi.org/10.1098/rsob.170087es
dc.relation.publisherversionhttps://royalsocietypublishing.org/doi/10.1098/rsob.170087es
dc.rightsopenAccesses
dc.rights.holderUniversidad Nacional de Rosarioes
dc.rights.holderTsai, Yi-Tinges
dc.rights.holderSalzman, Valentinaes
dc.rights.holderCabruja, Matías Ezequieles
dc.rights.holderGago, Gabrielaes
dc.rights.holderGramajo, Hugo Cesares
dc.rights.textAttribution 4.0 International (CC BY 4.0)es
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/*
dc.subjectMicrobiologyes
dc.subjectMycobacteriumes
dc.subjectMycolic Acidses
dc.subjectAcyl-CoAes
dc.subjectAcyl Coenzyme Aes
dc.subjectIsoniazides
dc.subjectTranscriptional regulationes
dc.titleRole of long-chain acyl-CoAs in the regulation of mycolic acid biosynthesis in mycobacteriaes
dc.typearticle
dc.typeartículo
dc.typepublishedVersion
dc.type.collectionarticulo
dc.type.versionpublishedVersiones

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