Abstract
One of the most important and exclusive characteristics of mycobacteria is their cell wall. Amongst its constituent components are two related families of glycosylated lipids, diphthioceranates and phthiocerol dimycocerosate (PDIM) and its variant phenolic glycolipids (PGL). PGL have been associated with cell wall impermeability, phagocytosis, defence against nitrosative and oxidative stress and, intriguingly, biofilm formation. In bacteria from the Mycobacterium tuberculosis complex (MTBC), the biosynthetic pathway of the phenolphthiocerol moiety of PGL depends upon the expression of several genes encoding type I polyketide synthases (PKS), namely ppsA-E and pks15/1 which constitute the PDIM + PGL locus, and that are highly conserved in PDIM/PGL-producing strains. Consensus has not been achieved regarding the genetic organization of pks15/1 locus and knowledge is lacking on its transcriptional signature. Here we explore publicly available datasets of transcriptome data (RNA-seq) from more than 100 MTBC experiments in 40 growth conditions to outline the transcriptional structure and signature of pks15/1, using a differential expression approach to infer the regulatory patterns involving these and related genes. We show that pks1 expression is highly correlated with fadD22, Rv2949c, lppX, fadD29 and, also, pks6 and pks12, with the first three putatively integrating into a polycistronic structure. We evidence dynamic transcriptional heterogeneity within the genes involved in phenolphtiocerol and phenolic glycolipid production, most exhibiting up-regulation upon acidic pH and antibiotic exposure and down-regulation under hypoxia, dormancy, and low/high iron concentration. We finally propose a model based on transcriptome data in which σD positively regulates pks1, pks15 and fadD22, while σB and σE factors exert negative regulation at an upper level.
Highlights
Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (Mtb) that remains a major public health concern
We focus on the transcriptional signature of genes comprising the biosynthetic pathway responsible for the synthesis of the phenolphthiocerol moiety of phenolic glycolipids (PGL), by investigating the expression of these genes when Mtb is grown under multiple stressors mimicking the host environment, namely pH variation, different carbon sources, limiting or excessive iron concentration, hypoxia, dormancy, phosphate depletion and antibiotic exposure
Encoded on the minus strand, from position 3291503 to 3296353 for pks1 and from position 3296350 to 3297840 for pks15, on the Mtb H37Rv genome, the pks1 and pks15 genes together encode a polyketide synthase with six identified domains involved in the synthesis of PGL
Summary
Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (Mtb) that remains a major public health concern. The mycobacterial cell wall, wherein Mycobacterium-specific components are located, is a crucial interface of Mtb and other pathogenic mycobacteria with the host [2]. Chiaradia and coworkers (2017) proposed a cell wall structure composed of three layers, namely the mycomembrane, arabinogalactan and peptidoglycan. This model proposes that the inner leaflet of the mycomembrane is composed of mycolic acids that are esterified to arabinogalactan, which in turn is covalently attached to peptidoglycan [3]. PGL are known to be associated with several cellular functions, namely impermeability of the cell wall, phagocytosis [4,5,6], defence mechanisms against nitrosative and oxidative stress [7] and to the ability of mycobacteria to form biofilms [8, 9]
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