Abstract
ABSTRACTPhosphatidylethanolamine is an abundant component of most cellular membranes whose physical and chemical properties modulate multiple aspects of organelle membrane dynamics. An evolutionarily ancient mechanism for producing phosphatidylethanolamine is to decarboxylate phosphatidylserine and the enzyme catalyzing this reaction, phosphatidylserine decarboxylase, localizes to the inner membrane of the mitochondrion. We characterize a second form of phosphatidylserine decarboxylase, termed PISD-LD, that is generated by alternative splicing of PISD pre-mRNA and localizes to lipid droplets and to mitochondria. Sub-cellular targeting is controlled by a common segment of PISD-LD that is distinct from the catalytic domain and is regulated by nutritional state. Growth conditions that promote neutral lipid storage in lipid droplets favors targeting to lipid droplets, while targeting to mitochondria is favored by conditions that promote consumption of lipid droplets. Depletion of both forms of phosphatidylserine decarboxylase impairs triacylglycerol synthesis when cells are challenged with free fatty acid, indicating a crucial role phosphatidylserine decarboxylase in neutral lipid storage. The results reveal a previously unappreciated role for phosphatidylserine decarboxylase in lipid droplet biogenesis.
Highlights
Phosphatidylserine (PS) and phosphatidylethanolamine (PE) are structurally related aminophospholipids that fulfill structural roles as components of organelle membranes, provide specific biochemical and cellular functions in a variety of processes such as apoptosis and autophagy, and serve as metabolic precursors to other lipids (Vance, 2008; Calzada et al, 2016)
Phosphatidylethanolamine is produced by multiple pathways, including by decarboxylation of PS by phosphatidylserine decarboxylase (PSD) (Vance, 2008; Calzada et al, 2016), an enzyme that localizes to the inner membrane of the mitochondrion in human cells (Borkenhagen et al, 1961; Dennis and Kennedy, 1972; Percy et al, 1983; Zborowski et al, 1983; Kuchler et al, 1986; Schuiki and Daum, 2009)
An alternatively spliced variant of PISD localizes to the lipid droplet the human genome contains a single locus encoding PSD, the genomes of many other eukaryotic organisms contain multiple genes encoding PSD enzymes that localize to other cellular compartments (Di Bartolomeo et al, 2017)
Summary
Phosphatidylserine (PS) and phosphatidylethanolamine (PE) are structurally related aminophospholipids that fulfill structural roles as components of organelle membranes, provide specific biochemical and cellular functions in a variety of processes such as apoptosis and autophagy, and serve as metabolic precursors to other lipids (Vance, 2008; Calzada et al, 2016). Consistent with this, a protein composed of just the unique segment of PISD-M (amino acids 1-107) fused to the amino terminus of GFP localized to mitochondria (Fig. 2).
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