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Reduced phosphatidylcholine synthesis suppresses the embryonic lethality of seipin deficiency
Jinglin Zhu1,2, Sin Man Lam1, Leilei Yang1
1State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China.
Abstract:
Seipin plays a vital role in lipid droplet homeostasis, and its deficiency causes congenital generalized lipodystrophy type II in humans. It is not known whether the physiological defects are all caused by cellular lipid droplet defects. Loss-of-function mutation of seip-1, the Caenorhabditis elegans seipin ortholog, causes embryonic lethality and lipid droplet abnormality. We uncover nhr-114 and spin-4 as two suppressors of seip-1 embryonic lethality. Mechanistically, nhr-114 and spin-4 act in the "B12-one-carbon cycle-phosphatidylcholine (PC)" axis, and reducing PC synthesis suppresses the embryonic lethality of seip-1 mutants. Conversely, PC deficiency enhances the lipid droplet abnormality of seip-1 mutants. The suppression of seip-1 embryonic lethality by PC reduction requires polyunsaturated fatty acid. In addition, the suppression is enhanced by the knockdown of phospholipid scramblase epg-3. Therefore, seipin and PC exhibit opposite actions in embryogenesis, while they function similarly in lipid droplet homeostasis. Our results demonstrate that seipin-mediated embryogenesis is independent of lipid droplet homeostasis.
Insights
Seipin deficiency causes embryonic lethality, but reducing phosphatidylcholine (PC) synthesis suppresses this. This suggests seipin-mediated embryogenesis is separate from lipid droplet regulation.
Area of Science:
- Cell Biology
- Genetics
- Biochemistry
Background:
- Seipin is crucial for lipid droplet homeostasis and its deficiency leads to lipodystrophy.
- The precise physiological role of seipin beyond lipid droplets remains unclear.
- Loss-of-function mutations in the seipin ortholog (seip-1) in C. elegans cause embryonic lethality and abnormal lipid droplets.
Purpose of the Study:
- To identify genetic suppressors of seip-1 loss-of-function.
- To elucidate the molecular mechanisms underlying seipin's role in embryogenesis.
- To investigate the relationship between seipin function, lipid droplet homeostasis, and embryogenesis.
Main Methods:
- Genetic screening in C. elegans to identify suppressors of seip-1 lethality.
- Analysis of the B12-one-carbon cycle-phosphatidylcholine (PC) synthesis pathway.
- Investigating the effects of PC reduction and polyunsaturated fatty acids on seip-1 mutants.
- Assessing the role of phospholipid scramblase (epg-3) in seipin function.
Main Results:
- Identified nhr-114 and spin-4 as suppressors of seip-1 embryonic lethality.
- Demonstrated that reducing phosphatidylcholine (PC) synthesis suppresses seip-1 lethality.
- Showed that PC deficiency exacerbates lipid droplet abnormalities in seip-1 mutants.
- Found that polyunsaturated fatty acids and phospholipid scramblase EPG-3 modulate the suppression of seip-1 lethality by PC reduction.
Conclusions:
- Seipin and PC have opposing roles in embryogenesis but similar roles in lipid droplet homeostasis.
- Seipin-mediated embryogenesis is independent of its role in lipid droplet homeostasis.
- The B12-one-carbon cycle-PC axis is a key regulator of seipin's function in development.
