Review
Structural remodeling, trafficking and functions of glycosylphosphatidylinositol-anchored proteins

https://doi.org/10.1016/j.plipres.2011.05.002Get rights and content

Abstract

Glycosylphosphatidylinositol (GPI) is a glycolipid that is covalently attached to proteins as a post-translational modification. Such modification leads to the anchoring of the protein to the outer leaflet of the plasma membrane. Proteins that are decorated with GPIs have unique properties in terms of their physical nature. In particular, these proteins tend to accumulate in lipid rafts, which are critical for the functions and trafficking of GPI-anchored proteins (GPI-APs). Recent studies mainly using mutant cells revealed that various structural remodeling reactions occur to GPIs present in GPI-APs as they are transported from the endoplasmic reticulum to the cell surface. This review examines the recent progress describing the mechanisms of structural remodeling of mammalian GPI-anchors, such as inositol deacylation, glycan remodeling and fatty acid remodeling, with particular focus on their trafficking and functions, as well as the pathogenesis involving GPI-APs and their deficiency.

Highlights

► We review recent progress in studies on glycosylphosphatidylinositol (GPI). ► Three different GPI remodeling reactions occur in GPI-anchored proteins during the transport to the cell surface. ► GPI is an important factor that defines the behaviors of GPI-anchored proteins, such as trafficking and signal transductions. ► Several inherited and acquired diseases such as paroxysmal nocturnal hemoglobinuria are caused by impaired GPI biosynthesis. ► GPI is implicated in pathogenesis of the prion disease.

Introduction

The presence of proteins anchored to the plasma membrane via phosphatidylinositol (PI) was first indicated in the 1970’s, because particular proteins were released from the surface following treatment with phosphatidylinositol-specific phospholipase C [1], [2], [3], [4], [5]. In the mid-1980’s compositional and structural data on Torpedo [6], human acetylcholinesterases [7], rat Thy-1 [8] and Trypanosoma brucei VSG [9], [10] reported the presence of GPI-anchors for these proteins. The complete GPI-anchor structures in T. brucei of VSG [11] and rat Thy-1 [12] were reported in 1988. Thus, the concept of the GPI was established. In the same period, several interesting findings on the biological significance of GPI-APs, such as signaling, protein trafficking and the accumulation in specialized microdomains, were reported, and paroxysmal nocturnal hemoglobinuria (PNH), an acquired hematopoietic stem cell disorder, turned out to be caused by a defect of GPI biosynthesis. These findings drew the attention of many researchers. Thereafter, intensive studies were performed to reveal the biosynthetic pathway and biological significance of GPI and GPI-APs. This review focuses the recent progress in the field of mammalian GPI-APs.

Section snippets

Structure of GPI

During the following decade after the complete GPI-anchor structures in T. brucei of VSG [11] and rat Thy-1 [12] were reported in 1988, the partial and complete structures of GPI-anchors in more than 20 proteins became available. The results of these studies showed that the backbone structure was conserved among eukaryotes such as mammals, yeast (Saccharomyces cerevisiae), protozoan parasites (T. brucei and Plasmodium falciparum) and a plant species (Pyrus communis). The conserved backbone

Structural GPI remodeling in GPI-APs

This section focuses on the structural GPI remodeling that occurs after the GPI is transferred to the protein. Schemes for the overall structural remodeling of mammalian GPI-APs and the significance are shown in Fig. 2, Fig. 3. Defects in GPI biosynthesis abrogate the surface expression of GPI-APs, whereas these remodeling events may allow surface expression, but affect their trafficking, cellular localization or functions. As mentioned above, the backbone structure of the GPI moiety in the

Association of GPI-APs with lipid rafts

A body of evidence strongly indicates the presence of a physiologically specialized microdomain; however, there is still controversy about the definition and existence because of the difficulties in characterization due to their proposed small size and dynamic nature [96], [97], [98], [99]. Common assays using detergent extraction with cold non-ionic detergents, such as Triton X-100, and cholesterol depletion with methyl-β-cyclodextrin are indirect and not conclusive because of possible

Paroxysmal nocturnal hemoglobinuria; PNH

Several interesting findings reported around the 1990’s on the biological significance of GPI-APs, such as intracellular signaling [96], [112], [113], protein trafficking [91], [131] and the accumulation in specialized microdomains [91], [110] led to many researchers showing significant interest in this field. In the same period, the main pathology of paroxysmal nocturnal hemoglobinuria (PNH), an acquired hematopoietic stem cell disorder, was revealed. The main symptom of PNH is anemia due to

Conclusions and perspective

About a quarter of a century has passed since the concept of the GPI was established, and many proteins that operate in the GPI biosynthetic pathway in the ER have been identified. A large body of in vitro evidence indicates that GPIs are critical for the function and transport of GPI-APs by virtue of their unique physical nature, particularly the affinity for lipid rafts. Nevertheless, the functional in vivo significance of GPIs is poorly understood and the absence of detailed information is

Acknowledgement

This work was supported by a grant from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

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