Genome-wide screen of Mycobacterium tuberculosis- infected macrophages identified the GID/CTLH complex as a determinant of intracellular bacterial growth.
bioRxiv
; 2024 May 08.
Article
em En
| MEDLINE
| ID: mdl-38766174
ABSTRACT
The eukaryotic 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 antimicrobial 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 10 predicted members of the GID/CTLH complex as determinants of intracellular growth of both Mtb and Salmonella serovar Typhimurium. We show that the antimicrobial properties of the GID/CTLH complex knockdown macrophages are mediated by enhanced GABAergic signaling, activated AMPK, increased autophagic flux and resistance to cell death. Meanwhile, Mtb isolated from GID/CTLH knockdown macrophages are nutritionally starved and oxidatively stressed. Our study identifies the GID/CTLH complex activity as broadly suppressive of host antimicrobial responses against intracellular bacterial infections.
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MEDLINE
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En
Ano de publicação:
2024
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Article