ARV1 is a component of the enzyme initiating glycosylphosphatidylinositol biosynthesis

TianTian Lu; Saori Umeshita; Kae Imanishi; Yicheng Wang; Yi-Shi Liu; Masamichi Nagae; Yuya Senoo; Kazutaka Ikeda; Morihisa Fujita; Taroh Kinoshita; Yoshiko Murakami

doi:10.1016/j.jbc.2025.110236

ARV1 is a component of the enzyme initiating glycosylphosphatidylinositol biosynthesis

J Biol Chem. 2025 May 14;301(6):110236. doi: 10.1016/j.jbc.2025.110236. Online ahead of print.

Authors

Affiliations

¹ Laboratory of Immunoglycobiology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan; Immunology Frontier Research Center, Osaka University, Osaka, Japan.
² Laboratory of Immunoglycobiology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.
³ Key Laboratory of Carbohydrate Chemistry and Biotechnology, School of Biotechnology, Jiangnan University, Wuxi, Jiangsu, China.
⁴ Laboratory of Biomolecule Analysis, Department of Applied Genomics, Kazusa DNA Research Institute, Chiba, Japan.
⁵ Institute for Glyco-core Research (iGCORE), Gifu University, Gifu, Japan.
⁶ Laboratory of Immunoglycobiology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan; Immunology Frontier Research Center, Osaka University, Osaka, Japan; Center for Infectious Disease Education and Research, Osaka University, Osaka, Japan.
⁷ Laboratory of Immunoglycobiology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan. Electronic address: yoshiko@biken.osaka-u.ac.jp.

Abstract

Glycosylphosphatidylinositol (GPI) serves as a membrane anchor of numerous cell surface proteins. It is synthesized in the endoplasmic reticulum from phosphatidylinositol (PI) by stepwise reactions and transferred to the C terminus of the protein. Defects in genes involved in GPI biosynthesis affect the expression of GPI-anchored proteins or their structure, causing the neurological disorder, inherited GPI deficiency. Individuals with ARV1 deficiency have symptoms resembling inherited GPI deficiency, but how ARV1 regulates GPI biosynthesis is poorly understood. Here, we show that ARV1 acts as a component of the enzyme initiating GPI biosynthesis, GPI N-acetylglucosaminyltransferase (GPI-GnT) complex, which forms a ring structure as predicted by AlphaFold3. ARV1 associates with PIGQ, a GPI-GnT component, and ARV1 mutants defective in this association lose their ability to enhance GPI-GnT activity, showing that association with PIGQ is critical for ARV1's function. ARV1-containing GPI-GnT used PI more efficiently than ARV1-less GPI-GnT in an in vitro enzyme assay. Collectively, our results suggest that ARV1 facilitates efficient recruitment of PI to GPI-GnT, thereby playing a critical role in the regulation of GPI-anchored protein expression.

Keywords: AlphaFold; GPI N-acetylglucosaminyltransferase complex; inherited GPI deficiency; lipidomics; phosphatidylinositol.