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Genome-wide screen of infected macrophages identified the GID/CTLH complex as a determinant of intracellular bacterial growth. | LitMetric
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 ( ) induced cytotoxicity in macrophages in a FACS based CRISPR genetic screen to identify host determinants of intracellular growth restriction. Our screen identified 5 ( , , , , ) of the 10 predicted members of the GID/CTLH complex as determinants of intracellular growth of both and 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, 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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