Publication date: Oct 29, 2024
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.
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Semantics
| Type | Source | Name |
|---|---|---|
| drug | DRUGBANK | Dextrose unspecified form |
| disease | IDO | role |
| disease | IDO | host |
| disease | MESH | Mtb |
| pathway | KEGG | Tuberculosis |
| disease | MESH | bacterial infections |
| disease | MESH | death |
| disease | IDO | pathogen |
| disease | MESH | infection |
| pathway | KEGG | Phagosome |
| pathway | KEGG | Lysosome |
| pathway | REACTOME | Fatty acids |
| drug | DRUGBANK | Cholesterol |
| disease | IDO | cell |
| disease | IDO | blood |
| disease | MESH | necrosis |
| disease | MESH | aids |
| pathway | REACTOME | Apoptosis |
| pathway | REACTOME | Autophagy |
| disease | IDO | production |
| drug | DRUGBANK | Spinosad |
| drug | DRUGBANK | BCG vaccine |
| disease | IDO | replication |
| disease | IDO | virulence |
| disease | IDO | bacteria |
| drug | DRUGBANK | Estradiol |
| disease | IDO | assay |
| disease | IDO | colony |
| disease | IDO | protein |
| pathway | REACTOME | Signal Transduction |