Sec and Tat mediated secretion safeguards Mycobacterium tuberculosis membrane homeostasis
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Protein secretion drives Mycobacterium tuberculosis ( Mtb ) physiology and pathogenesis, yet a unified picture of the machinery and its role in cell membrane homeostasis is still lacking. By comprehensively curating published evidence, we assembled a systems-level map of Mtb secretion encompassing 92 components and 198 mechanistic reactions across Sec, Tat, and ESX pathways. The secretory components identified were integrated with high-throughput ChIP-Seq and transcriptome datasets to elucidate the regulation of the secretion system. Using CRISPRi, conditional depletion of SecA1 or TatA impaired growth in vitro and survival ex vivo . Quantitative secretome revealed decreased export of SecA1- and TatA-dependent substrates, with enrichment of cytosolic proteins in culture filtrates, indicating increased membrane permeability. Membrane proteomics showed depletion dependent increased metabolic/lipid-degrading proteins and decreased cell-wall/cell-process proteins, consistent with loss of membrane stability. Ultrastructural defects and increased ethidium bromide uptake confirmed impaired membrane integrity. Together, our multi-omics and functional genetics established SecA1 and TatA as essential guardians of Mtb membrane integrity which provided valuable datasets and a framework for secretion-dependent Mtb pathogenesis.
