Tse, S. Y. | Search bioRxiv

bioRxiv2023

Transcriptional suppression of sphingolipid catabolism controls pathogen resistance in C. elegans

Sphingolipids are required for diverse biological functions and are degraded by specific catabolic enzymes. However, the mechanisms that regulate sphingolipid catabolism are not known. Here we characterize a transcriptional axis that regulates sphingolipid breakdown to control resistance against bacterial infection. From an RNAi screen for transcriptional regulators of pathogen resistance in the nematode C. elegans, we identified the nuclear hormone receptor nhr-66, a ligand-gated transcription factor homologous to human hepatocyte nuclear factor 4. Tandem chromatin immunoprecipitation-sequencing and RNA sequencing experiments revealed that NHR-66 is a transcriptional repressor, which directly targets sphingolipid catabolism genes. Transcriptional de-repression of two sphingolipid catabolic enzymes in nhr-66 loss-of-function mutants drives the breakdown of sphingolipids, which enhances host susceptibility to infection with the bacterial pathogen Pseudomonas aeruginosa. These data define transcriptional control of sphingolipid catabolism in the regulation of cellular sphingolipids, a process that is necessary for pathogen resistance.

immunology↗

bioRxiv2022

Bacterial pattern recognition in C. elegans by a nuclear hormone receptor

Pattern recognition of bacterial products by host receptors is essential for innate immunity in many metazoans. Curiously, the nematode lineage lost canonical mechanisms of bacterial pattern recognition. Whether other immune receptors evolved in their place is not known. Here, we characterize the first bacterial pattern recognition receptor and its natural ligand in the nematode Caenorhabditis elegans. We show that the C. elegans nuclear hormone receptor NHR-86/HNF4 senses phenazine-1-carboxamide (PCN), a metabolite produced by pathogenic strains of Pseudomonas aeruginosa. PCN binds to the ligand-binding domain of NHR-86/HNF4, a ligand-gated transcription factor, and activates an anti-pathogen transcriptional program in intestinal epithelial cells that provides protection against P. aeruginosa. These data de-orphan a nuclear hormone receptor and demonstrate that surveillance of metabolite signals from bacteria allows nematodes to identify virulent pathogens in their environment that are poised to cause disease.

immunology↗