biostudies-literatureSimwela NVU.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious DiseasesNIAID NIH HHSU.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)Mueller Health FoundationU.S. Department of Health & Human Services | NIH | NIH Office of the DirectorNIH HHSU.S. Department of Health & Human Services | NIH | NIH Office of the Director (OD)9322https://www.ebi.ac.uk/biostudies/studies/S-EPMC11522665biostudies-literatureUnknown15(1)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,Nature communicationsGenome-wide screen of Mycobacterium tuberculosis-infected macrophages revealed GID/CTLH complex-mediated modulation of bacterial growth.PMC11522665S10 OD032135AI155319R01 AI155319U19 AI162598R01 AI172433OD032135AI162598AI172433T32AI007349T32 AI007349Simwela NVSassetti CMJaecklein EJohnston LAltier CBitar PPRussell DGfalseGenome-wide screen of Mycobacterium tuberculosis-infected macrophages revealed GID/CTLH complex-mediated modulation of bacterial growth.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,2024-01-01T00:00:00Z2024 Oct2025-04-05T09:12:24.934Z2025-04-05T09:12:24.934ZS-EPMC115226653947245710.1038/s41467-024-53637-z