INVESTIGADORES
GAGO Gabriela Marisa
artículos
Título:
Role of long-chain acyl-CoAs in the regulation of mycolic acid biosynthesis in mycobacteria
Autor/es:
TSAI, YI TING; SALZMAN, VALENTINA; CABRUJA, MATÍAS; GAGO, GABRIELA* (CORRESPONDING); GRAMAJO, HUGO
Revista:
Open Biology
Editorial:
Royal Society
Referencias:
Año: 2017 vol. 7
Resumen:
One of the dominant features of the biology of Mycobacterium tuberculosis,and other mycobacteria, is the mycobacterial cell envelope with its exceptionalcomplex composition. Mycolic acids are major and very specificcomponents of the cell envelope and play a key role in its architecture andimpermeability. Biosynthesis of mycolic acid (MA) precursors requires twotypes of fatty acid synthases, FAS I and FAS II, which should work in concertin order to keep lipid homeostasis tightly regulated. Both FAS systemsare regulated at their transcriptional level by specific regulatory proteins.FasR regulates components of the FAS I system, whereas MabR and FadRregulate components of the FAS II system. In this article, by constructing atight mabR conditional mutant in Mycobacterium smegmatis mc2155, wedemonstrated that sub-physiological levels of MabR lead to a downregulationof the fasII genes, inferring that this protein is a transcriptionalactivator of the FAS II system. In vivo labelling experiments and lipidomicstudies carried out in the wild-type and the mabR conditional mutantdemonstrated that under conditions of reduced levels of MabR, there is aclear inhibition of biosynthesis of MAs, with a concomitant change intheir relative composition, and of other MA-containing molecules. Thesestudies also demonstrated a change in the phospholipid composition ofthe membrane of the mutant strain, with a significant increase of phosphatidylinositol.Gel shift assays carried out with MabR and PfasII as a probe inthe presence of different chain-length acyl-CoAs strongly suggest that moleculeslonger than C18 can be sensed by MabR to modulate its affinity forthe operator sequences that it recognizes, and in that way switch on or offthe MabR-dependent promoter. Finally, we demonstrated the direct role ofMabR in the upregulation of the fasII operon genes after isoniazid treatment.