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

Bahr, L.; Amrit, F. R.; Silvia, P. E.; Bui, D.; Wayhs, B.; Choe, M.; Osman, G.; Naim, N.; Champion, M.; Shen, J.; Irazoqui, J. E.; Olsen, C. P.; Ghazi, A.

doi:10.1101/2025.07.14.664648

bioRxiv · 10.1101/2025.07.14.664648

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

Bahr, L.·Amrit, F. R.·Silvia, P. E.·Bui, D.·Wayhs, B.·Choe, M.·Osman, G.·Naim, N.·Champion, M.·Shen, J.·Irazoqui, J. E.·Olsen, C. P.·Ghazi, A.

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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.

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Bahr, L., Amrit, F. R., Silvia, P. E., Bui, D., Wayhs, B., Choe, M., Osman, G., Naim, N., Champion, M., Shen, J., Irazoqui, J. E., Olsen, C. P., Ghazi, A.. 2025-07-18. LIPL-1 and LIPL-2 are TCER-1-regulated Lysosomal Lipases with Distinct Roles in Immunity and Fertility. https://doi.org/10.1101/2025.07.14.664648

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