Suppression of Sphingolipid Catabolism by a Nuclear Hormone Receptor Promotes Pathogen Resistance in C. elegans
Faculty AdvisorRead Pukkila-Worley, M.D.
UMass Chan AffiliationsMorningside Graduate School of Biomedical Sciences
Document TypeDoctoral Dissertation
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AbstractSphingolipids are key structural components of cell membranes and function as signaling molecules that are required for diverse biological functions in all metazoan animals. Here we characterize a novel immunometabolic pathway that regulates sphingolipid catabolism to promote resistance to 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 HNF4. Tandem chromatin immunoprecipitation-sequencing (ChIP-seq) and RNA sequencing (RNA-seq) experiments revealed that NHR-66 is a transcriptional repressor, which directly targets sphingolipid catabolism and stress response 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. Genetic epistasis analysis revealed that nhr-66 functions with the PPARɑ homolog nhr-49 for host defense against P. aeruginosa and in the regulation of sphingolipid catabolism genes. These data define transcriptional control of sphingolipid catabolism in the regulation of cellular sphingolipid and ceramide levels, revealing an immunometabolic axis that is required for host survival during pathogen infection.
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/52360
Funding and AcknowledgementsThis research was supported by R01 AI130289 (to R.P.W.), R01 AI159159 (to R.P.W.), a diversity supplement to R01 AI159159 (to M.A.N. and R.P.W.), R21 AI163430 (to R.P.W.), and T32 GM107000 (to M.A.N.)
RightsCopyright © 2023 Mohamad A. Nasrallah
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