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全基因组筛选结核分枝杆菌感染的巨噬细胞揭示了 GID/CTLH 复合物介导的细菌生长调控。

Genome-wide screen of Mycobacterium tuberculosis-infected macrophages revealed GID/CTLH complex-mediated modulation of bacterial growth.

机构信息

Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA.

Department of Population Medicine and Diagnostic Sciences, Cornell University, Ithaca, NY, USA.

出版信息

Nat Commun. 2024 Oct 29;15(1):9322. doi: 10.1038/s41467-024-53637-z.

DOI:10.1038/s41467-024-53637-z
PMID:39472457
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11522665/
Abstract

The eukaryotic Glucose Induced Degradation/C-Terminal to LisH (GID/CTLH) complex is a highly conserved E3 ubiquitin ligase involved in a broad range of biological processes. However, a role of this complex in host anti-microbial defenses has not been described. We exploited Mycobacterium tuberculosis (Mtb) induced cytotoxicity in macrophages in a FACS based CRISPR genetic screen to identify host determinants of intracellular Mtb growth restriction. Our screen identified 5 (GID8, YPEL5, WDR26, UBE2H, MAEA) of the 12 predicted members of the GID/CTLH complex as determinants of intracellular growth of both Mtb and Salmonella serovar Typhimurium. We show that the anti-microbial properties of the GID/CTLH complex knockout macrophages are mediated by enhanced GABAergic signaling, activated AMPK, increased autophagic flux and resistance to Mtb induced necrotic cell death. Meanwhile, Mtb isolated from GID/CTLH knockout macrophages are nutritionally starved and oxidatively stressed. Our study identifies the GID/CTLH complex activity as broadly suppressive of host anti-microbial responses against intracellular bacterial infections.

摘要

真核生物葡萄糖诱导降解/C 末端到 LisH（GID/CTLH）复合物是一种高度保守的 E3 泛素连接酶，参与广泛的生物学过程。然而，该复合物在宿主抗微生物防御中的作用尚未被描述。我们利用基于 FACS 的 CRISPR 遗传筛选，研究了巨噬细胞中结核分枝杆菌（Mtb）诱导的细胞毒性，以鉴定宿主对细胞内 Mtb 生长限制的决定因素。我们的筛选确定了 GID/CTLH 复合物的 12 个预测成员中的 5 个（GID8、YPEL5、WDR26、UBE2H、MAEA）作为 Mtb 和沙门氏菌血清型鼠伤寒菌细胞内生长的决定因素。我们表明，GID/CTLH 复合物敲除巨噬细胞的抗微生物特性是通过增强 GABA 能信号、激活 AMPK、增加自噬通量和抵抗 Mtb 诱导的坏死性细胞死亡来介导的。同时，从 GID/CTLH 敲除巨噬细胞中分离出的 Mtb 受到营养饥饿和氧化应激的影响。我们的研究确定了 GID/CTLH 复合物的活性广泛抑制了宿主对细胞内细菌感染的抗微生物反应。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a4bb/11522665/c10a23b76b7e/41467_2024_53637_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a4bb/11522665/e4b785996fe8/41467_2024_53637_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a4bb/11522665/6dcdea5afadb/41467_2024_53637_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a4bb/11522665/401435769731/41467_2024_53637_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a4bb/11522665/95dc1019d55c/41467_2024_53637_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a4bb/11522665/3e502e81acd7/41467_2024_53637_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a4bb/11522665/90c65694bd88/41467_2024_53637_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a4bb/11522665/c10a23b76b7e/41467_2024_53637_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a4bb/11522665/e4b785996fe8/41467_2024_53637_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a4bb/11522665/6dcdea5afadb/41467_2024_53637_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a4bb/11522665/401435769731/41467_2024_53637_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a4bb/11522665/95dc1019d55c/41467_2024_53637_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a4bb/11522665/3e502e81acd7/41467_2024_53637_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a4bb/11522665/90c65694bd88/41467_2024_53637_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a4bb/11522665/c10a23b76b7e/41467_2024_53637_Fig7_HTML.jpg

相似文献

[1]
Genome-wide screen of Mycobacterium tuberculosis-infected macrophages revealed GID/CTLH complex-mediated modulation of bacterial growth.

Nat Commun. 2024-10-29

[2]
Genome-wide screen of infected macrophages identified the GID/CTLH complex as a determinant of intracellular bacterial growth.

bioRxiv. 2024-5-8

[3]
Non-canonical substrate recognition by the human WDR26-CTLH E3 ligase regulates prodrug metabolism.

Mol Cell. 2024-5-16

[4]
The multi-subunit GID/CTLH E3 ubiquitin ligase promotes cell proliferation and targets the transcription factor Hbp1 for degradation.

Elife. 2018-6-18

[5]
Structural and Functional Insights into GID/CTLH E3 Ligase Complexes.

Int J Mol Sci. 2022-5-24

[6]
Skraban-Deardorff intellectual disability syndrome-associated mutations in WDR26 impair CTLH E3 complex assembly.

FEBS Lett. 2024-5

[7]
Molecular phylogeny of a RING E3 ubiquitin ligase, conserved in eukaryotic cells and dominated by homologous components, the muskelin/RanBPM/CTLH complex.

PLoS One. 2013-10-15

[8]
Interplay between β-propeller subunits WDR26 and muskelin regulates the CTLH E3 ligase supramolecular complex.

Commun Biol. 2024-12-19

[9]
The mammalian CTLH complex is an E3 ubiquitin ligase that targets its subunit muskelin for degradation.

Sci Rep. 2019-7-8

[10]
Multisite phosphorylation dictates selective E2-E3 pairing as revealed by Ubc8/UBE2H-GID/CTLH assemblies.

Mol Cell. 2024-1-18

引用本文的文献

[1]
Incorporation of macrophage immune stresses into an assay for drug tolerance in intracellular .

bioRxiv. 2025-5-9

[2]
Using host and bacterial genetic approaches to define virulence strategies and protective immunity during infection.

mSphere. 2025-5-27

[3]
The Role of Inflammation in the Pathogenesis of Comorbidity of Chronic Obstructive Pulmonary Disease and Pulmonary Tuberculosis.

Int J Mol Sci. 2025-3-7

[4]
Impaired fatty acid import or catabolism in macrophages restricts intracellular growth of .

Elife. 2025-3-13

[5]
Muskelin is a substrate adaptor of the highly regulated Drosophila embryonic CTLH E3 ligase.

EMBO Rep. 2025-3

[6]
How macrophage heterogeneity affects tuberculosis disease and therapy.

Nat Rev Immunol. 2025-5

[7]
Impaired fatty acid import or catabolism in macrophages restricts intracellular growth of .

bioRxiv. 2025-1-11

[8]
Muskelin acts as a substrate receptor of the highly regulated CTLH E3 ligase during the maternal-to-zygotic transition.

bioRxiv. 2024-7-1

本文引用的文献

[1]
Rethinking the burden of latent tuberculosis to reprioritize research.

Nat Microbiol. 2024-5

[2]
Toxin-Antitoxin system of Mycobacterium tuberculosis: Roles beyond stress sensor and growth regulator.

Tuberculosis (Edinb). 2023-12

[3]
Iron limitation in M. tuberculosis has broad impact on central carbon metabolism.

Commun Biol. 2022-7-9

[4]
Structural and Functional Insights into GID/CTLH E3 Ligase Complexes.

Int J Mol Sci. 2022-5-24

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Nat Rev Microbiol. 2022-11

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Proteomic analysis of ubiquitination substrates reveals a CTLH E3 ligase complex-dependent regulation of glycolysis.

FASEB J. 2021-9

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MAEA is an E3 ubiquitin ligase promoting autophagy and maintenance of haematopoietic stem cells.

Nat Commun. 2021-5-4

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