Proteomics reveals coordinated stress adaptation by a MazF toxin to conserve carbon, sustain central metabolism, and preserve PDIM biosynthesis in Mycobacterium tuberculosis

ABSTRACT: In response to host-generated stresses, Mycobacterium tuberculosis (Mtb) reprograms its physiology in myriad ways to establish and maintain an infection, yet the signals that underlie this transformation are not well defined. The abundant toxin-antitoxin (TA) systems harbored in the Mtb genome, including eleven in the mazEF family, are thought to act as stress sensors, yet their roles are largely unknown. Although TA systems from other bacteria are generally thought to impart reversible growth arrest in response to stress, the exquisite specificity of Mtb tRNase toxins instead portends a more nuanced role. Here, we used a proteomics approach to track de novo protein synthesis to uncover molecular events initiated by the Mtb MazF-mt9 toxin (MazF7, Rv2063A). First, we documented striking enrichment of enzymes and transporters derived from the contiguous 36 gene region for phthiocerol dimycocerosate (PDIM) synthesis without an accompanying increase in PDIM lipid production. This paradox was reconciled by concomitant downregulation of proteins comprising the Mce1 transporter (imports host fatty acids), cholesterol breakdown, and β oxidation enzymes (limiting the PDIM precursor methylmalonyl-CoA). Thus, increased catalytic efficiency of the PDIM pathway appears to offset substrate starvation to ensure adequate production of PDIMs essential for Mtb early immune escape and virulence. Finally, isocitrate lyase 1 levels also increased, which in this context are expected to primarily catalyze the glyoxylate shunt to sustain central carbon metabolism while minimizing carbon loss. These exacting proteomic signatures are paralleled within the bedaquiline-treated Mtb transcriptome, highlighting a critical role for MazF-mt9 in orchestrating Mtb stress survival.

INSTRUMENT(S):

ORGANISM(S): Mycobacterium Tuberculosis H37rv

SUBMITTER: Bruno Abbadi  

LAB HEAD: Nancy Woychik

PROVIDER: PXD052177 | Pride | 2026-03-06

REPOSITORIES: Pride