CDS2 expression regulates de novo phosphatidic acid synthesis

Area of Science:

• Lipid metabolism
• Cell signaling
• Mammalian cell biology

Background:

• CDP-DG is crucial for de novo synthesis of PI.
• CDS enzymes (CDS1 and CDS2) convert PA to CDP-DG.
• CDS2 deletion in macrophages alters lipid profiles.

Purpose of the Study:

• Investigate the role of CDS2 in lipid homeostasis.
• Understand the impact of CDS2 deficiency on PI synthesis and signaling.
• Explore the consequences of altered lipid metabolism on cellular functions.

Main Methods:

• Genetic deletion of CDS2 in primary mouse macrophages.
• Stable isotope labeling with 13C6- and 13C6D7-glucose.
• Analysis of phospholipid species, de novo synthesis rates, and calcium homeostasis.

Main Results:

• CDS2 deficiency led to increased PA, CDP-DG, DG, and TG levels.
• De novo PI synthesis rate was minimally affected, but PA synthesis increased substantially.
• CDS2-deficient macrophages showed impaired PI synthesis during GPCR stimulation and defective calcium homeostasis.

Conclusions:

• Mammalian cells increase de novo PA synthesis to maintain PI levels when CDS capacity is reduced.
• CDS2 deficiency impacts PI synthesis during signaling and affects calcium homeostasis, likely via increased basal PA.
• This study offers a new interpretation of CDS2 deletion effects on lipid metabolism and signaling.