LIPL-1 and LIPL-2 are TCER-1-regulated lysosomal lipases with distinct roles in immunity and fertility

Reproduction and immunity are energy intensive processes that often compete for resources, leading to trade-offs across species. Lipid metabolism integrates these processes, particularly during stressful conditions such as pathogenic infections, yet the underlying molecular mechanisms remain poorly understood. TCER-1, the C. elegans homolog of mammalian TCERG1, suppresses immunity and promotes fertility, especially upon maternal infection. Here, we show that TCER-1 coordinates this balance by regulating two conserved lysosomal lipases, lipl-1 and lipl-2. Using transcriptomic, lipidomic, and molecular-genetic analyses, we demonstrate that both lipases mediate infection-induced lipid remodeling but with distinct outcomes: lipl-1 promotes immunity, whereas, lipl-2 does not. LIPL-1 catalyzes the accumulation of specific ceramide species, including Cer 17:1;O2/24:0, whose supplementation rescues the immunity phenotypes of tcer-1;lipl-1 mutants and enhances post-infection survival of wild-type animals. Both lipases influence fertility with lipl-2 playing a key role in maintaining embryonic-eggshell integrity during maternal infection and aging. Remarkably, expression of human lysosomal acid lipase (hLAL/LIPA), the ortholog of 'lipl' genes, restores immunity defects triggered by lipl-1 loss and enhances immune resilience but does not significantly ameliorate the fertility defects. Together, these findings reveal distinct roles for lipl-1 and lipl-2 in modulating lipid species that link immune defense, reproductive fitness and healthspan through a potentially conserved mechanism.