Acyl-coA synthases (ACSs) produce fatty acyl-CoAs that are used in metabolic and signaling pathways. Metazoans have a large number of ACS genes with differing expression patterns and substrate preferences, but the physiological roles of most ACS genes are unknown. Here, we focused on the C. elegans acyl CoA synthase, ACS-3, which is known to regulate fat uptake and de novo fat synthesis through the conserved nuclear hormone receptor,
nhr-25. We performed microarray analysis of
acs-3 mutants to elucidate the
acs-3-regulated transcription program. This analysis revealed an enrichment among differentially regulated genes of those involved in lipid metabolism, pathogen and wounding responses, and sterol binding genes, among others. As the immunity genes were the most represented gene class, we performed pathogen sensitivity assays to test the phenotypic consequences of this immune gene regulation. Interestingly,
acs-3 mutants were hypersensitive to the fungal pathogen D. coniospora, but only mildly sensitive to the bacterial pathogen P. aeruginosa.
acs-3 mutation suppressed
nhr-25 mutant sensitivity to P. aeruginosa, yet surprisingly microarray analysis of
nhr-25(RNAi) animals revealed significant overlap with the
acs-3 mutant transcriptome, with an enrichment of pathogen response genes. The upregulation of pathogen response genes in
acs-3(
ft5) mutants and following
nhr-25 reduction-of-function (rf) does not appear to be due to a constitutive osmotic response or defective cuticle barrier, two potential explanations for the
acs-3(
ft5) and
nhr-25(rf) expression of innate immunity genes in the absence of pathogen exposure. Together, these data indicate that ACS-3 promotes resistance to the fungal pathogen, D. coniospora and regulates innate immunity genes through an unknown mechanism. Potential roles for ACS-3 in innate immunity are discussed.