Genome-wide screen of Mycobacterium tuberculosis-infected macrophages revealed GID/CTLH complex-mediated modulation of bacterial growth.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
29 Oct 2024
29 Oct 2024
Historique:
received:
23
05
2024
accepted:
18
10
2024
medline:
30
10
2024
pubmed:
30
10
2024
entrez:
30
10
2024
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 39472457
doi: 10.1038/s41467-024-53637-z
pii: 10.1038/s41467-024-53637-z
doi:
Substances chimiques
Ubiquitin-Protein Ligases
EC 2.3.2.27
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
9322Subventions
Organisme : U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)
ID : AI155319
Organisme : U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)
ID : AI162598
Organisme : U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)
ID : AI172433
Organisme : U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)
ID : T32AI007349
Organisme : U.S. Department of Health & Human Services | NIH | NIH Office of the Director (OD)
ID : OD032135
Informations de copyright
© 2024. The Author(s).
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