RRC ID 80953
Author Nasrallah MA, Peterson ND, Szumel ES, Liu P, Page AL, Tse SY, Wani KA, Tocheny CE, Pukkila-Worley R.
Title Transcriptional suppression of sphingolipid catabolism controls pathogen resistance in C. elegans.
Journal PLoS Pathog
Abstract 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.
Volume 19(10)
Pages e1011730
Published 2023-10-1
DOI 10.1371/journal.ppat.1011730
PMID 37906605
PMC PMC10637724
MeSH Animals Caenorhabditis elegans* / microbiology Caenorhabditis elegans Proteins* / genetics Caenorhabditis elegans Proteins* / metabolism Gene Expression Regulation Humans Sphingolipids / genetics Sphingolipids / metabolism Transcription Factors / metabolism
C.elegans tm1547