Preferential use of alkyl-acyl phosphatidylinositol for GPI biosynthesis and diagnostic potential of lipidomics for inherited GPI deficiencies

Glycosylphosphatidylinositol-anchored proteins (GPI-APs) are attached to the cell surface via a glycolipid anchor, GPI, whose conserved core is synthesized from phosphatidylinositol (PI) in the endoplasmic reticulum through a series of enzymatic reactions. Most PI species in mammalian cells contain diacylglycerol, whereas GPI-APs predominantly possess 1-alkyl-2-acylglycerol. The basis for this characteristic lipid structure has remained unclear. Lipidomic analysis revealed that 1-alkyl-2-acyl PIs, although minor components of cellular PI, are preferentially used by GPI-N-acetylglucosaminyltransferase, which catalyzes the first step of GPI biosynthesis. GPI intermediates containing 1-alkyl-2-acylglycerol were further enriched in subsequent biosynthetic steps, resulting in mature GPIs primarily harboring this lipid species. We demonstrate that a 1-alkyl-containing precursor lipid derived from peroxisomes, likely 1-alkyl-glyceronephosphate, contributes to the formation of 1-alkyl-2-acyl PIs. Disruption of glyceronephosphate O-acyltransferase (GNPAT) or alkylglycerone phosphate synthase (AGPS), the first two enzymes of the peroxisomal ether-lipid pathway, abolished 1-alkyl-2-acyl PI, yielding GPI-APs containing only diacylglycerol. Lipidomic profiling of GPI biosynthetic intermediates in GPI-defective cells revealed accumulation of defective-step-specific intermediates, enabling the use of this approach for diagnosing inherited GPI deficiency (IGD).

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Subject (DDC)

570 - Biowissenschaften, Biologie

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ISSN

0021-9258
1067-8816
1083-351X

Language

English

Created during FHNW affiliation

Yes

Strategic action fields FHNW

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Published

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peer-reviewed

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Gold

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Citation

Li, X., Imanishi, K., Umeshita, S., Senoo, Y., Guerrero, P. A., Varon, D., Ikeda, K., Kinoshita, T., & Murakami, Y. (2026). Preferential use of alkyl-acyl phosphatidylinositol for GPI biosynthesis and diagnostic potential of lipidomics for inherited GPI deficiencies. Journal of Biological Chemistry, 302(3). https://doi.org/10.1016/j.jbc.2026.111256

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