{"doi":"10.1101/2025.09.04.674216","title":"Sec and Tat mediated secretion safeguards <i>Mycobacterium tuberculosis</i> membrane homeostasis","abstract":"Abstract 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.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":574248,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9364,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1481680,"name":"Uppada Jagadeeshwari","orcid":"0000-0002-1266-2330","position":1,"is_corresponding":false},{"id":504428,"name":"Sanjeev Sinha","orcid":"0000-0001-8060-4231","position":2,"is_corresponding":false},{"id":1482042,"name":"Yashasvi Bhat","orcid":null,"position":3,"is_corresponding":false},{"id":1481681,"name":"Sidra Khan","orcid":"0000-0001-9403-8795","position":4,"is_corresponding":false},{"id":1481682,"name":"S. Rajaram","orcid":"0000-0002-2446-9642","position":5,"is_corresponding":false},{"id":1482043,"name":"Evanjalee Albert Arokiyaraj","orcid":null,"position":6,"is_corresponding":false},{"id":1481683,"name":"Gagan Deep Jhingan","orcid":"0009-0005-7491-8994","position":7,"is_corresponding":false},{"id":660231,"name":"Nisheeth Agarwal","orcid":"0000-0001-9203-3026","position":8,"is_corresponding":false},{"id":1269400,"name":"Areejit Samal","orcid":"0000-0002-6796-9604","position":9,"is_corresponding":false},{"id":452646,"name":"Vinay Kumar Nandicoori","orcid":"0000-0002-5682-4178","position":10,"is_corresponding":false},{"id":1482041,"name":"Priyadarshini Sanyal","orcid":null,"position":0,"is_corresponding":true}],"reference_count":84,"raw_metadata":null,"created_at":"2026-07-19T02:57:40.686992Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}