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ER-dependent membrane repair of mycobacteria-induced vacuole damage

Several intracellular pathogens, such as Mycobacterium tuberculosis, damage endomembranes to access the cytosol and subvert innate immune responses. The host counteracts endomembrane damage by recruiting repair machineries that retain the pathogen inside the vacuole. Here, we show that the endoplasm...

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Autores principales: Anand, Aby, Mazur, Anna-Carina, Rosell-Arevalo, Patricia, Franzkoch, Rico, Breitsprecher, Leonhard, Listian, Stevanus A., Hüttel, Sylvana V., Müller, Danica, Schäfer, Deise G., Vormittag, Simone, Hilbi, Hubert, Maniak, Markus, Gutierrez, Maximiliano G., Barisch, Caroline
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Microbiology 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10653851/
https://www.ncbi.nlm.nih.gov/pubmed/37676004
http://dx.doi.org/10.1128/mbio.00943-23
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author Anand, Aby
Mazur, Anna-Carina
Rosell-Arevalo, Patricia
Franzkoch, Rico
Breitsprecher, Leonhard
Listian, Stevanus A.
Hüttel, Sylvana V.
Müller, Danica
Schäfer, Deise G.
Vormittag, Simone
Hilbi, Hubert
Maniak, Markus
Gutierrez, Maximiliano G.
Barisch, Caroline
author_facet Anand, Aby
Mazur, Anna-Carina
Rosell-Arevalo, Patricia
Franzkoch, Rico
Breitsprecher, Leonhard
Listian, Stevanus A.
Hüttel, Sylvana V.
Müller, Danica
Schäfer, Deise G.
Vormittag, Simone
Hilbi, Hubert
Maniak, Markus
Gutierrez, Maximiliano G.
Barisch, Caroline
author_sort Anand, Aby
collection PubMed
description Several intracellular pathogens, such as Mycobacterium tuberculosis, damage endomembranes to access the cytosol and subvert innate immune responses. The host counteracts endomembrane damage by recruiting repair machineries that retain the pathogen inside the vacuole. Here, we show that the endoplasmic reticulum (ER)-Golgi protein oxysterol-binding protein (OSBP) and its Dictyostelium discoideum homolog OSBP8 are recruited to the Mycobacterium-containing vacuole (MCV) dependent on the presence of the ESX-1 secretion system, suggesting that their mobilization is associated with membrane damage. Lack of OSBP8 causes a hyperaccumulation of phosphatidylinositol-4-phosphate (PI4P) on the MCV and decreased cell viability. OSBP8-depleted cells had reduced lysosomal and degradative capabilities of their vacuoles that favored mycobacterial growth. In agreement with a potential role of OSBP8 in membrane repair, human macrophages infected with M. tuberculosis recruited OSBP in an ESX-1-dependent manner. These findings identified an ER-dependent repair mechanism for restoring MCVs in which OSBP8 functions to equilibrate PI4P levels on damaged membranes. IMPORTANCE: Tuberculosis still remains a global burden and is one of the top infectious diseases from a single pathogen. Mycobacterium tuberculosis, the causative agent, has perfected many ways to replicate and persist within its host. While mycobacteria induce vacuole damage to evade the toxic environment and eventually escape into the cytosol, the host recruits repair machineries to restore the MCV membrane. However, how lipids are delivered for membrane repair is poorly understood. Using advanced fluorescence imaging and volumetric correlative approaches, we demonstrate that this involves the recruitment of the endoplasmic reticulum (ER)-Golgi lipid transfer protein OSBP8 in the Dictyostelium discoideum/Mycobacterium marinum system. Strikingly, depletion of OSBP8 affects lysosomal function accelerating mycobacterial growth. This indicates that an ER-dependent repair pathway constitutes a host defense mechanism against intracellular pathogens such as M. tuberculosis.
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spelling pubmed-106538512023-09-07 ER-dependent membrane repair of mycobacteria-induced vacuole damage Anand, Aby Mazur, Anna-Carina Rosell-Arevalo, Patricia Franzkoch, Rico Breitsprecher, Leonhard Listian, Stevanus A. Hüttel, Sylvana V. Müller, Danica Schäfer, Deise G. Vormittag, Simone Hilbi, Hubert Maniak, Markus Gutierrez, Maximiliano G. Barisch, Caroline mBio Research Article Several intracellular pathogens, such as Mycobacterium tuberculosis, damage endomembranes to access the cytosol and subvert innate immune responses. The host counteracts endomembrane damage by recruiting repair machineries that retain the pathogen inside the vacuole. Here, we show that the endoplasmic reticulum (ER)-Golgi protein oxysterol-binding protein (OSBP) and its Dictyostelium discoideum homolog OSBP8 are recruited to the Mycobacterium-containing vacuole (MCV) dependent on the presence of the ESX-1 secretion system, suggesting that their mobilization is associated with membrane damage. Lack of OSBP8 causes a hyperaccumulation of phosphatidylinositol-4-phosphate (PI4P) on the MCV and decreased cell viability. OSBP8-depleted cells had reduced lysosomal and degradative capabilities of their vacuoles that favored mycobacterial growth. In agreement with a potential role of OSBP8 in membrane repair, human macrophages infected with M. tuberculosis recruited OSBP in an ESX-1-dependent manner. These findings identified an ER-dependent repair mechanism for restoring MCVs in which OSBP8 functions to equilibrate PI4P levels on damaged membranes. IMPORTANCE: Tuberculosis still remains a global burden and is one of the top infectious diseases from a single pathogen. Mycobacterium tuberculosis, the causative agent, has perfected many ways to replicate and persist within its host. While mycobacteria induce vacuole damage to evade the toxic environment and eventually escape into the cytosol, the host recruits repair machineries to restore the MCV membrane. However, how lipids are delivered for membrane repair is poorly understood. Using advanced fluorescence imaging and volumetric correlative approaches, we demonstrate that this involves the recruitment of the endoplasmic reticulum (ER)-Golgi lipid transfer protein OSBP8 in the Dictyostelium discoideum/Mycobacterium marinum system. Strikingly, depletion of OSBP8 affects lysosomal function accelerating mycobacterial growth. This indicates that an ER-dependent repair pathway constitutes a host defense mechanism against intracellular pathogens such as M. tuberculosis. American Society for Microbiology 2023-09-07 /pmc/articles/PMC10653851/ /pubmed/37676004 http://dx.doi.org/10.1128/mbio.00943-23 Text en Copyright © 2023 Anand et al. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Research Article
Anand, Aby
Mazur, Anna-Carina
Rosell-Arevalo, Patricia
Franzkoch, Rico
Breitsprecher, Leonhard
Listian, Stevanus A.
Hüttel, Sylvana V.
Müller, Danica
Schäfer, Deise G.
Vormittag, Simone
Hilbi, Hubert
Maniak, Markus
Gutierrez, Maximiliano G.
Barisch, Caroline
ER-dependent membrane repair of mycobacteria-induced vacuole damage
title ER-dependent membrane repair of mycobacteria-induced vacuole damage
title_full ER-dependent membrane repair of mycobacteria-induced vacuole damage
title_fullStr ER-dependent membrane repair of mycobacteria-induced vacuole damage
title_full_unstemmed ER-dependent membrane repair of mycobacteria-induced vacuole damage
title_short ER-dependent membrane repair of mycobacteria-induced vacuole damage
title_sort er-dependent membrane repair of mycobacteria-induced vacuole damage
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10653851/
https://www.ncbi.nlm.nih.gov/pubmed/37676004
http://dx.doi.org/10.1128/mbio.00943-23
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