Cunqi Ye Lab investigates fundamental biology of membrane phospholipids and metabolic regulations that are crucial for human health.
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Phospholipids are the major components of all cell membranes. Organelle biogenesis and membrane dynamics require phospholipid synthesis for membrane expansion and remodeling. While the obvious role of the regulation of phospholipid synthesis is to confer the endomembrane system with unique compositions, how this metabolic control impacts homeostatic regulation is an open question and poorly understood. Our research reported for the first time that phospholipid synthesis can consume substantial amounts of cellular S-adenosylmethionine, a major methyl donor, leading to reconfiguration of methylation-based regulatory events, including methylation of the histones and a major protein phosphatase. These findings suggest that phospholipid synthesis can necessitate coordination with metabolic control of cellular homeostasis through modulating cellular levels of key intermediary metabolites. We are currently investigating physiological roles of this metabolic control.
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Cellular metabolism is essential to sustain life and underlies a vast number of mechanisms of pathogenesis. Among thousands of small-molecule metabolites, we are particularly interested in key intermediary metabolites that are shared by metabolic reactions for building cellular blocks and chemical modifications for regulatory purposes. These metabolites include S-adenosylmethionine (SAM) and acetyl-CoA, and they are kinetically stable but thermodynamically activated. We found that cellular SAM is substantially consumed by methylation of phospholipids and the histones. This bulk turnover of SAM can influences cell growth and the redox environment, as it subsequently fuels the synthesis of cysteine and glutathione. We also discovered that a unique carboxyl methylation of the major phosphatase PP2A can act as a cellular gauge of SAM. Metabolic processes that alter cellular SAM levels can thus signal SAM-sensitive PP2A methylation for phosphoproteomic control. We demonstrated a PP2A-governed mechanism whereby histone demethylation is activated through a resultant hyperphosphorylation of the H3K36 demethylase enzyme. In addition to SAM-based crosstalk between metabolism and regulation, we are also investigating how acetyl-CoA bridges phospholipid synthesis to regulatory mechanisms for metabolic fitness under calorie restriction.
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Abnormal phospholipid compositions are associated with numerous human diseases. Among them, a variety of human genetic disorders is caused by mutations in metabolic genes that disrupt synthesis of different species of phospholipids. For example, Liberfarb syndrome is caused by a homozygous recessive defect in phosphatidylserine decarboxylase (PISD); Lenz-Majewski syndrome is caused by gain-of-function mutations in the phosphatidylserine synthase 1 (PTDSS1) gene; and Barth syndrome is caused by mutations in the tafazzin gene encoding a cardiolipin remodeling enzyme. Surprisingly, very little is known about cellular and molecular bases for pathologies with aberrant phospholipid metabolism. My group will use yeast and mammalian cells as well as mouse models to explore unknown biological mechanisms. We are particularly interested in the role of phospholipid synthesis in the nervous system.
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