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结核分枝杆菌毒素的分泌和转运。

Toxin secretion and trafficking by Mycobacterium tuberculosis.

机构信息

Department of Microbiology, University of Alabama at Birmingham, 609 Bevill Biomedical Research Building, 845 19th Street South, Birmingham, AL, 35294, USA.

University of Colorado Boulder, Jennie Smoly Caruthers Biotechnology Building B255, 3415 Colorado Avenue, Boulder, CO, 80303, USA.

出版信息

Nat Commun. 2021 Nov 15;12(1):6592. doi: 10.1038/s41467-021-26925-1.

DOI:10.1038/s41467-021-26925-1
PMID:34782620
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8593097/
Abstract

The tuberculosis necrotizing toxin (TNT) is the major cytotoxicity factor of Mycobacterium tuberculosis (Mtb) in macrophages. TNT is the C-terminal domain of the outer membrane protein CpnT and gains access to the cytosol to kill macrophages infected with Mtb. However, molecular mechanisms of TNT secretion and trafficking are largely unknown. A comprehensive analysis of the five type VII secretion systems of Mtb revealed that the ESX-4 system is required for export of CpnT and surface accessibility of TNT. Furthermore, the ESX-2 and ESX-4 systems are required for permeabilization of the phagosomal membrane in addition to the ESX-1 system. Thus, these three ESX systems need to act in concert to enable trafficking of TNT into the cytosol of Mtb-infected macrophages. These discoveries establish new molecular roles for the two previously uncharacterized type VII secretion systems ESX-2 and ESX-4 and reveal an intricate link between toxin secretion and phagosomal permeabilization by Mtb.

摘要

结核分枝杆菌坏死毒素（TNT）是分枝杆菌在巨噬细胞中的主要细胞毒性因子。TNT 是外膜蛋白 CpnT 的 C 末端结构域，可进入细胞质杀死感染分枝杆菌的巨噬细胞。然而，TNT 的分泌和运输的分子机制在很大程度上是未知的。对分枝杆菌的五个 VII 型分泌系统的全面分析表明，ESX-4 系统是 CpnT 输出和 TNT 表面可及性所必需的。此外，ESX-2 和 ESX-4 系统除了 ESX-1 系统外，还需要使吞噬体膜穿孔。因此，这三个 ESX 系统需要协同作用，才能使 TNT 运输到感染分枝杆菌的巨噬细胞的细胞质中。这些发现为以前未被表征的两种 VII 型分泌系统 ESX-2 和 ESX-4 确立了新的分子作用，并揭示了分枝杆菌毒素分泌和吞噬体穿孔之间的复杂联系。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dee7/8593097/7b718cae6e33/41467_2021_26925_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dee7/8593097/e815642ef9bb/41467_2021_26925_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dee7/8593097/0d42609d443f/41467_2021_26925_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dee7/8593097/1a2c1994035c/41467_2021_26925_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dee7/8593097/594af132694b/41467_2021_26925_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dee7/8593097/c2cbfd9eb13d/41467_2021_26925_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dee7/8593097/7b718cae6e33/41467_2021_26925_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dee7/8593097/e815642ef9bb/41467_2021_26925_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dee7/8593097/0d42609d443f/41467_2021_26925_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dee7/8593097/1a2c1994035c/41467_2021_26925_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dee7/8593097/594af132694b/41467_2021_26925_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dee7/8593097/c2cbfd9eb13d/41467_2021_26925_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dee7/8593097/7b718cae6e33/41467_2021_26925_Fig6_HTML.jpg

相似文献

[1]
Toxin secretion and trafficking by Mycobacterium tuberculosis.

Nat Commun. 2021-11-15

[2]
Mycobacterium tuberculosis Toxin CpnT Is an ESX-5 Substrate and Requires Three Type VII Secretion Systems for Intracellular Secretion.

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[3]
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[4]
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[5]
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[6]
The tuberculosis necrotizing toxin kills macrophages by hydrolyzing NAD.

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[7]
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Proc Natl Acad Sci U S A. 2022-3-15

[8]
ESX-1-secreted substrate protein EspC promotes mycobacterial survival through endoplasmic reticulum stress-mediated apoptosis.

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[9]
Pore-forming Esx proteins mediate toxin secretion by Mycobacterium tuberculosis.

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[10]
The Role of ESX-1 in Pathogenesis.

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[2]
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[3]
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Nat Rev Microbiol. 2025-6-30

[4]
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J Bacteriol. 2025-5-22

[5]
Deletion of ESX-3 and ESX-4 secretion systems in Mycobacterium abscessus results in highly impaired pathogenicity.

Commun Biol. 2025-2-3

[6]
The antibacterial activity of a prophage-encoded fitness factor is neutralized by two cognate immunity proteins.

J Biol Chem. 2024-12

[7]
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[8]
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Microbiol Spectr. 2024-11-8

[9]
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[10]
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本文引用的文献

[1]
Structure and dynamics of a mycobacterial type VII secretion system.

Nature. 2021-5

[2]
Mycobacterium tuberculosis Toxin CpnT Is an ESX-5 Substrate and Requires Three Type VII Secretion Systems for Intracellular Secretion.

mBio. 2021-3-2

[3]
Pore-forming Esx proteins mediate toxin secretion by Mycobacterium tuberculosis.

Nat Commun. 2021-1-15

[4]
Mammalian membrane trafficking as seen through the lens of bacterial toxins.

Cell Microbiol. 2020-4

[5]
PE/PPE proteins mediate nutrient transport across the outer membrane of .

Science. 2020-3-6

[6]
Species-specific secretion of ESX-5 type VII substrates is determined by the linker 2 of EccC.

Mol Microbiol. 2020-7

[7]
Comprehensive analysis of iron utilization by Mycobacterium tuberculosis.

PLoS Pathog. 2020-2-18

[8]
Architecture of the mycobacterial type VII secretion system.

Nature. 2019-10-9

[9]
Comprehensive Characterization of the Attenuated Double Auxotroph ΔΔ as an Alternative to H37Rv.

Front Microbiol. 2019-8-20

[10]
Mycobacterium tuberculosis Type VII Secretion System Effectors Differentially Impact the ESCRT Endomembrane Damage Response.

mBio. 2018-11-27

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