Loss of the ESX-5 secretion locus in Mycobacterium tuberculosis reshapes the mycomembrane and enhances ESX-1 substrate secretion

• 成果类型: Article
• 署名作者: Koleske, Benjamin; Rajagopalan, Saranathan; Schill, Courtney; Lun, Shichun; Vilcheze, Catherine; Das, Lahari; Gupta, Manish; Martinez-Martinez, Yazmin B.; Bishai, William R.; Jacobs Jr, William R.
• 署名单位: Johns Hopkins University; Montefiore Medical Center; Albert Einstein College of Medicine; Yeshiva University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-13309
• DOI: 10.1073/pnas.2509997122
• 发表日期: 2025-09-09
• 关键词: outer-membrane; bovis bcg; virulence; SYSTEM; protein; sequence; marinum; signal; TRANSFORMATION; attenuation

摘要

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 Desx5 mutant. In examining other ESX systems, we found that ESX-1 substrate levels were increased in both the CF and OMM fractions of the Desx5 mutant. Conversely, the ESX-3 locus was transcriptionally repressed upon ESX-5 deletion. We noted that the Desx5 mutant had altered morphology in the form of wrinkled distortions of the bacterial surface. Likewise, we identified increased susceptibility of the Desx5 mutant to a variety of large (molecular weight >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.