Role of long-chain acyl-CoAs in the regulation of mycolic acid biosynthesis in mycobacteria
One 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 imp...
Guardado en:
| Autores principales: | , , , , |
|---|---|
| Formato: | article artículo publishedVersion |
| Lenguaje: | Inglés |
| Publicado: |
Royal Society
2020
|
| Materias: | |
| Acceso en línea: | http://hdl.handle.net/2133/19534 http://hdl.handle.net/2133/19534 |
| Aporte de: |
| Sumario: | One 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. |
|---|