{"doi":"10.1073/pnas.2509997122","title":"Loss of the ESX-5 secretion locus in <i>Mycobacterium tuberculosis</i> reshapes the mycomembrane and enhances ESX-1 substrate secretion","abstract":"The ESX-5 secretion system, uniquely found in slow-growing mycobacteria, is predicted to secrete over 150 proteins across the inner membrane of Mycobacterium tuberculosis ( M.tb ). Although many of these substrates are believed to promote M.tb virulence, most remain poorly characterized. Here, we use a complete locus deletion strain of ESX-5 in M.tb to examine the molecular changes caused by a broad loss in ESX-5 secretory substrates. We confirmed the selective loss of PE/PPE proteins secreted by ESX-5 into both the culture filtrate (CF) and outer mycomembrane (OMM) fractions of the M.tb ∆esx5 mutant. In examining other ESX systems, we found that ESX-1 substrate levels were increased in both the CF and OMM fractions of the ∆esx5 mutant. Conversely, the ESX-3 locus was transcriptionally repressed upon ESX-5 deletion. We noted that the ∆esx5 mutant had altered morphology in the form of wrinkled distortions of the bacterial surface. Likewise, we identified increased susceptibility of the ∆esx5 mutant to a variety of large (molecular weight &gt;550 g/mol) antimicrobial compounds, suggesting that an intact ESX-5 system is required for M.tb to exclude such molecules. Our findings suggest that removing the ESX-5 system from M.tb fundamentally alters the properties of the mycobacterial OMM and impacts the expression and secretion activity of other ESX systems.","journal":"Proceedings of the National Academy of Sciences","year":2025,"id":524352,"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":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9544,"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":518114,"name":"Rajagopalan Saranathan","orcid":"0000-0003-2201-8028","position":1,"is_corresponding":false},{"id":911162,"name":"Courtney Schill","orcid":"0000-0002-2841-7612","position":2,"is_corresponding":false},{"id":352337,"name":"Shichun Lun","orcid":null,"position":3,"is_corresponding":false},{"id":282324,"name":"Catherine Vilchèze","orcid":"0000-0001-5960-6670","position":4,"is_corresponding":false},{"id":1148547,"name":"Lahari Das","orcid":"0000-0002-8951-9532","position":5,"is_corresponding":false},{"id":1303259,"name":"Manish Gupta","orcid":"0000-0002-8782-6096","position":6,"is_corresponding":false},{"id":279912,"name":"Yazmin B. Martinez-Martinez","orcid":null,"position":7,"is_corresponding":false},{"id":241544,"name":"William R. Bishai","orcid":"0000-0002-8734-4118","position":8,"is_corresponding":false},{"id":361264,"name":"William R. Jacobs","orcid":"0000-0003-3321-3080","position":9,"is_corresponding":false},{"id":829473,"name":"Benjamin Koleske","orcid":"0000-0002-1479-218X","position":0,"is_corresponding":true}],"reference_count":79,"raw_metadata":null,"created_at":"2026-07-19T02:50:12.083054Z","pmid":"40901885","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":[]}