Transcriptional suppression of sphingolipid catabolism controls pathogen resistance in C. elegans.
Mohamad A NasrallahNicholas D PetersonElizabeth S SzumelPengpeng LiuAmanda L PageSamantha Y TseKhursheed A WaniClaire E TochenyRead Pukkila-WorleyPublished in: PLoS pathogens (2023)
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.
Keyphrases
- transcription factor
- gene expression
- nuclear factor
- pseudomonas aeruginosa
- candida albicans
- single cell
- genome wide identification
- heat shock
- dna binding
- genome wide
- dna damage
- endothelial cells
- cystic fibrosis
- dna methylation
- dna repair
- escherichia coli
- oxidative stress
- drug resistant
- high throughput
- multidrug resistant
- immune response
- deep learning
- acinetobacter baumannii
- bioinformatics analysis