Revisiting the expression signature of pks15/1 unveils regulatory patterns controlling phenolphtiocerol and phenolglycolipid production in pathogenic mycobacteria

Abstract

One of the most relevant and exclusive characteristics of mycobacteria is its cell wall, composed by mycolic acids. Amid these 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, supposedly, biofilm formation. In bacteria from the Mycobacterium tuberculosis complex, 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 constituting the PDIM + PGL locus, highly conserved in PDIM/PGL-producing strains. Consensus has not been achieved regarding the genetic organization of pks15/1 locus and little effort has been put on the disclosure of its transcriptional signature. Here we explore publicly available datasets of transcriptome data (RNA-seq) from more than 100 experiments in 40 growth conditions to outline the transcriptional structure and signature of pks15/1 and use a differential expression approach to infer the regulatory patterns involving these and related genes. We show that pks1 is highly correlated with fadD22, Rv2949c, lppX, fadD29 and, also, pks6 and pks12, with the first three putatively integrating a polycistronic structure. We evidence dynamic heterogeneity of transcription within the genes involved in phenolphtiocerol and phenolglycolipid 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 {sigma}D positively regulates pks1, pks15 and fadD22, while {sigma}B and {sigma}E factors exert negative regulation at an upper level.