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Vol. 17, Issue 12, 5253-5264, December 2006

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PER1 Is Required for GPI-Phospholipase A₂ Activity and Involved in Lipid Remodeling of GPI-anchored Proteins

Morihisa Fujita^*, Mariko Umemura^*,, Takehiko Yoko-o^*, and Yoshifumi Jigami^*,

*Research Center for Glycoscience, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraki 305-8566, Japan; and Graduate School of Life and Environmental Science, University of Tsukuba, Tsukuba, Ibaraki 305-8572, Japan

Submitted August 16, 2006; Revised September 14, 2006; Accepted September 27, 2006
Monitoring Editor: Sean Munro

Glycosylphoshatidylinositol (GPI) anchors are remodeled during their transport to the cell surface. Newly synthesized proteins are transferred to a GPI anchor, consisting of diacylglycerol with conventional C16 and C18 fatty acids, whereas the lipid moiety in mature GPI-anchored proteins is exchanged to either diacylglycerol containing a C26:0 fatty acid in the sn-2 position or ceramide in Saccharomyces cerevisiae. Here, we report on PER1, a gene encoding a protein that is required for the GPI remodeling pathway. We found that GPI-anchored proteins could not associate with the detergent-resistant membranes in per1 cells. In addition, the mutant cells had a defect in the lipid remodeling from normal phosphatidylinositol (PI) to a C26 fatty acid–containing PI in the GPI anchor. In vitro analysis showed that PER1 is required for the production of lyso-GPI, suggesting that Per1p possesses or regulates the GPI-phospholipase A₂ activity. We also found that human PERLD1 is a functional homologue of PER1. Our results demonstrate for the first time that PER1 encodes an evolutionary conserved component of the GPI anchor remodeling pathway, highlighting the close connection between the lipid remodeling of GPI and raft association of GPI-anchored proteins.

Address correspondence to: Yoshifumi Jigami (jigami.yoshi{at}aist.go.jp)

Abbreviations used: CFW, calcofluor white; DRM, detergent-resistant membrane; ER, endoplasmic reticulum; GPI, glycosylphosphatidylinositol; IPC, inositolphosphorylceramide; IPC/B, IPC consisting of phytosphingosine and a C26:0 fatty acid; IPC/C, IPC consisting of phytosphingosine and a hydroxylated C26:0 fatty acid; mRFP, monomeric red fluorescent protein; pG1, phosphatidylinositol with a C26:0 fatty acid in sn-2 position; PI, phosphatidylinositol; PLA₂, phospholipase A₂; TLC, thin-layer chromatography.

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