LIPL-1 and LIPL-2 are TCER-1-regulated Lysosomal Lipases with Distinct Roles in Immunity and Fertility

Abstract

Reproduction and immunity are fundamental, energy intensive processes that often compete for resources, leading to trade-offs observed across diverse species. Lipid metabolism plays a crucial role in integrating these processes, particularly during stressful conditions such as pathogenic infections. Yet the molecular mechanisms governing this integration 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 regulates two conserved lysosomal lipases, lipl-1 and lipl-2, to balance reproduction, immunity and lifespan. Using transcriptomic, lipidomic, and molecular-genetic analyses, we demonstrate that while both lipl-1 and lipl-2 mediate infection-induced lipid remodeling, lipl-1 enhances immunity and catalyzes the accumulation of ceramide species linked to stress response and longevity, whereas, lipl-2 unexpectedly does not. Both lipases contribute towards fertility outcomes, but lipl-2 is especially critical for maintaining embryonic-eggshell integrity during maternal infection and aging. Strikingly, expression of human lysosomal acid lipase (LAL), the ortholog of lipl genes, rescues the immune defects triggered by lipl-l loss and enhances immune resilience. Together, these findings uncover functionally distinct roles for lipl-1 and lipl-2 in modulating lipid species that shape immune fitness, healthspan and reproductive health, and suggest a potentially conserved mechanism by which lipid metabolism links fertility and immunity.