Like other multicellular organisms, the model nematode C. elegans responds to infection by inducing the expression of defense genes. Among the genes upregulated in response to a natural fungal pathogen is
nlp-29, encoding an antimicrobial peptide. In a screen for mutants that fail to express
nlp-29 following fungal infection, we isolated alleles of
tpa-1, homologous to the mammalian protein kinase C (PKC) delta. Through epistasis analyses, we demonstrate that C. elegans PKC acts through the
p38 MAPK pathway to regulate
nlp-29. This involves G protein signaling and specific C-type phospholipases acting upstream of PKCdelta. Unexpectedly and unlike in mammals,
tpa-1 does not act via D-type protein kinases, but another C. elegans PKC gene,
pkc-3, functions nonredundantly with
tpa-1 to control
nlp-29 expression. Finally, the tribbles-like kinase
nipi-3 acts upstream of PKCdelta in this antifungal immune signaling cascade. These findings greatly expand our understanding of the pathways involved in C. elegans innate immunity.