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Ministerio de Economia y Competitividad SAF2016-77433-R Rafael Prados-Rosales Ministerio de Economia y Competitividad PID2019-110240RB-I00 Rafael Prados-Rosales Ministerio de Economia y Competitividad PID2022-136611OB-I00 Rafael Prados-Rosales National Institutes of Health R01AI162821 Rafael Prados-Rosales Ministerio de Ciencia e Innovacion PID2019-106859GA-I00 Joaquin Sanz Wellcome Trust 212197/Z/19/Z Jamie K Hobbs Laia Pasquina-Lemonche Swedish Research Council VR2018-02823 Felipe Cava Swedish Research Council VR2018-05882 Felipe Cava Knut and Alice Wallenberg Foundation KAW2012.0184 Felipe Cava Kempe Foundation Felipe Cava Government of Aragon, Spain B49-23R (NeuroBioSys) Joaquin Sanz Ministerio de Economia y Competitividad Severo Ochoa Excellence Accreditation (CICbioGUNE) SEV-2016- 0644 Ainhoa Palacios Felix Elortza Mikel Azkargorta Ministerio de Ciencia e Innovacion RYC-2017-23560 Joaquin Sanz The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. For the purpose of Open Access, the authors have applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission.

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Maintenance of cell wall remodeling and vesicle production are connected in Mycobacterium tuberculosis

Publicado en:eLife. 13 RP94982- - 2025-02-17 13(), DOI: 10.7554/eLife.94982

Autores: Salgueiro-Toledo, Vivian C; Salgueiro-Toledo, Vivian C; Bertol, Jorge; Gutierrez, Claude; Serrano-Mestre, Jose L; Serrano-Mestre, Jose L; Ferrer-Luzon, Noelia; Vazquez-Iniesta, Lucia; Palacios, Ainhoa; Pasquina-Lemonche, Laia; Espaillat, Akbar; Lerma, Laura; Weinrick, Brian; Lavin, Jose L; Lavin, Jose L; Elortza, Felix; Azkargorta, Mikel; Prieto, Alicia; Buendia-Nacarino, Pilar; Luque-Garcia, Jose L; Luque-Garcia, Jose L; Neyrolles, Olivier; Cava, Felipe; Hobbs, Jamie K; Hobbs, Jamie K; Sanz, Joaquin; Prados-Rosales, Rafael

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Pathogenic and nonpathogenic mycobacteria secrete extracellular vesicles (EVs) under various conditions. EVs produced by Mycobacterium tuberculosis (Mtb) have raised significant interest for their potential in cell communication, nutrient acquisition, and immune evasion. However, the relevance of vesicle secretion during tuberculosis infection remains unknown due to the limited understanding of mycobacterial vesicle biogenesis. We have previously shown that a transposon mutant in the LCP-related gene virR (virRmut) manifested a strong attenuated phenotype during experimental macrophage and murine infections, concomitant to enhanced vesicle release. In this study, we aimed to understand the role of VirR in the vesicle production process in Mtb. We employ genetic, transcriptional, proteomics, ultrastructural, and biochemical methods to investigate the underlying processes explaining the enhanced vesiculogenesis phenomenon observed in the virRmut. Our results establish that VirR is critical to sustain proper cell permeability via regulation of cell envelope remodeling possibly through the interaction with similar cell envelope proteins, which control the link between peptidoglycan and arabinogalactan. These findings advance our understanding of mycobacterial extracellular vesicle biogenesis and suggest that these set of proteins could be attractive targets for therapeutic intervention.

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