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

Area of Science:

• Molecular Biology
• Immunology
• Metabolism

Background:

• Reproduction and immunity are vital, energy-demanding processes often in conflict, leading to trade-offs.
• Lipid metabolism is critical for integrating these functions, especially during infections, but underlying mechanisms are unclear.
• TCER-1, a homolog of mammalian TCERG1 in *C. elegans*, suppresses immunity and aids fertility, particularly after maternal infection.

Purpose of the Study:

• To investigate the molecular mechanisms by which TCER-1 integrates reproduction and immunity through lipid metabolism.
• To elucidate the distinct roles of the lysosomal lipases LIPL-1 and LIPL-2 in balancing these fundamental biological processes.

Main Methods:

• Transcriptomic and lipidomic analyses to profile gene expression and lipid changes.
• Molecular-genetic approaches in *C. elegans* to study lipase function.
• Functional assays assessing immunity, fertility, and lifespan.

Main Results:

• TCER-1 regulates the lysosomal lipases LIPL-1 and LIPL-2, impacting lipid remodeling during infection.
• LIPL-1 enhances immunity and promotes ceramide accumulation linked to stress response and longevity.
• LIPL-2 is crucial for embryonic-eggshell integrity during maternal infection and aging, though it does not directly impact immunity in the same way as LIPL-1.
• Human lysosomal acid lipase (LAL) rescues immune defects from *lipl-1* loss, indicating conserved function.

Conclusions:

• LIPL-1 and LIPL-2 have distinct roles in modulating lipid metabolism to influence immune fitness, healthspan, and reproductive health.
• Lipid metabolism, via these lipases, provides a conserved mechanism linking fertility and immunity.
• Findings highlight potential therapeutic targets for enhancing immune resilience and reproductive health.