Abstract
Cell membranes contain various transporter proteins, some of which are responsible for transferring amino acids across membrane. In this study, we report another class of carrier proteins, termed Serinc1-5, that incorporates a polar amino acid serine into membranes and facilitates the synthesis of two serine-derived lipids, phosphatidylserine and sphingolipids. Serinc is a unique protein family that shows no amino acid homology to other proteins but is highly conserved among eukaryotes. The members contain 11 transmembrane domains, and rat Serinc1 protein co-localizes with lipid biosynthetic enzymes in endoplasmic reticulum membranes. A Serinc protein forms an intracellular complex with key enzymes involved in serine and sphingolipid biosyntheses, and both functions, serine synthesis and membrane incorporation, are linked to each other. In the rat brain, expression of Serinc1 and Serinc2 mRNA was rapidly up-regulated by kainate-induced seizures in neuronal cell layers of the hippocampus. In contrast, myelin throughout the brain is enriched with Serinc5, which was down-regulated in the hippocampus by seizures. These results indicate a novel mechanism linking neural activity and lipid biosynthesis.
Highlights
IntroductionThis study has demonstrated for the first time that a protein family having 11 transmembrane domains facilitates the incorporation of serine into both phosphatidylserine and sphingolipids
The present study suggests that Serinc proteins play a pivotal role in the regulation of lipid biosynthesis
Eukaryotic endoplasmic reticulum (ER) membranes were enriched with Serinc protein, where it bound directly to the key enzyme of sphingolipid biosynthesis, serine palmitoyltransferase
Summary
This study has demonstrated for the first time that a protein family having 11 transmembrane domains facilitates the incorporation of serine into both phosphatidylserine and sphingolipids. This is a function novel to proteins and is referred to as Serinc (serine incorporator). Some of the family members were reported to be differentially expressed in some environments; TDE1 (corresponding to Serinc3) expression was increased in both human lung tumors and mouse testicular tumors [8, 9]; and TPO1 (corresponding to Serinc5) expression was developmentally induced in a terminal differentiation stage of cultured oligodendrocytes [10] These findings implied the important role of this family in multiple aspects of cell physiology, but the function of this family remained unknown. Because sphingolipids are major components of lipid rafts, Serinc is likely to function as a lipid raft maker in activity-dependent neural plasticity and oncogenic transformation
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