Lipid remodeling of GPI-anchored proteins and its function

doi:10.1016/j.bbagen.2007.08.009

Biochimica et Biophysica Acta (BBA) - General Subjects

Volume 1780, Issue 3, March 2008, Pages 410-420

https://doi.org/10.1016/j.bbagen.2007.08.009 Get rights and content

Abstract

Many proteins are attached to the cell surface via a conserved post-stranslational modification, the glycosylphosphatidylinositol (GPI) anchor. GPI-anchored proteins are functionally diverse, but one of their most striking features is their association with lipid microdomains, which consist mainly of sphingolipids and sterols. GPI-anchored proteins modulate various biological functions when they are incorporated into these specialized domains. The biosynthesis of GPI and its attachment to proteins occurs in the endoplasmic reticulum. The lipid moieties of GPI-anchored proteins are further modified during their transport to the cell surface, and these remodeling processes are essential for the association of proteins with lipid microdomains. Recently, several genes required for GPI lipid remodeling have been identified in yeast and mammalian cells. In this review, we describe the pathways for lipid remodeling of GPI-anchored proteins in yeast and mammalian cells, and discuss how lipid remodeling affects the association of GPI-anchored proteins with microdomains in cellular events.

Introduction

A number of proteins are modified with glycosylphosphatidylinositol (GPI). GPI anchoring is a post-translational modifications conserved among yeast, protozoans, plants, and animals [1], [2], [3]. The existence of GPI anchors and their modification of proteins were identified in the 1980s, and the complete structures of the GPI anchors of Trypanosoma brucei variant surface glycoprotein and rat brain Thy-1 were determined in 1988 [4], [5]. These structures provided the impetus for studying the biosynthesis and modification pathways for the GPI anchor, as well as for studying the function of individual GPI-anchored proteins. More than 150 plasma membrane proteins are presently known to be anchored by GPI in mammalian cells. GPI-anchored proteins are functionally diverse and are important for signal transduction, cell–cell interaction, cell adhesion, and host defense [2], [6]. In addition, some GPI-anchored proteins function as receptors for viruses and toxins [2]. In the genome of the yeast Saccharomyces cerevisiae, more than 60 genes are predicted to encode GPI-anchored proteins which play important roles in cell wall biogenesis and cell wall assembly [7]. Some GPI-anchored proteins are localized at the plasma membrane, whereas others are further processed at the plasma membrane and are covalently linked via the GPI moiety to β1,6-glucan components of the cell wall.

GPI anchors have variations in the side chain and lipid moieties, but the core structure is conserved among all species. The biosynthesis of GPI is essential for the growth of yeasts and bloodstream forms of protozoan, and for embryonic development in mammals [8], [9], [10]. The biosynthesis and attachment of GPI to proteins occur by a series of sequential reactions on the endoplasmic reticulum (ER) membrane. Phosphatidylinositol is modified by the stepwise additions of sugars and ethanolaminephosphates (EtN-P), forming a complete precursor lipid in the ER [11], [12]. Most genes involved in the GPI biosynthetic pathway have been characterized in mammalian cells and yeast. To date, more than 20 genes are known to be directly involved in this reaction [11], [12].

GPI-anchored proteins have unique properties that are different from those of soluble or membrane proteins. One of the most striking features of GPI-anchored proteins is their association with specialized lipid domain, called microdomains or lipid rafts [13], [14]. Microdomains or lipid rafts are assumed to be sphingolipid- and sterol-rich membranes and can be biochemically isolated as a detergent-resistant membrane (DRM) fraction [13], [15]. There is no satisfactory simple definition of microdomains, but certain lipids form specific membrane structures that function as a platform for intracellular signaling and are required for the selective transport of proteins [14], [15], [16]. The structure of GPI is important for the integration of GPI-anchored proteins into lipid microdomains. Although the GPI anchor is synthesized from phosphatidylinositol (PI) containing unsaturated fatty acyl chains at the sn-2 position, the lipid moieties of the GPI anchor are exchanged after GPI attachment to proteins in both yeast and mammalian cells [17], [18] (Fig. 1). This lipid remodeling process of GPI-anchored proteins is essential for their association with the lipid microdomains. In this review, we discuss the genes involved in the lipid remodeling pathways of GPI-anchored proteins and their functions in yeast and mammalian cells.

Section snippets

Evidence of lipid remodeling from structural analysis

Lipid remodeling of GPI-anchors has been well characterized in the African trypanosome T. brucei [19]. The fatty acids of the GPI intermediates are replaced by myristic acid (C14:0) through sequential deacylation and reacylation reactions at the sn-2 position followed by the sn-1 position before the GPI is attached to the protein in the bloodstream form of T. brucei [1], [19], [20]. Trypanosoma cruzi has GPI anchors containing ceramides, even though ceramides are not the first substrate in GPI

Yeast BST1 and mammalian PGAP1 involved in GPI inositol deacylation

Early in the GPI biosynthesis pathway, the inositol on the GPI intermediate GlcN-PI is acylated by yeast Gwt1p or mammalian PIG-W [40], [41]. This acylation step is clearly critical for efficient GPI biosynthesis and attachment to proteins, as the amounts of GPI-anchored proteins are greatly decreased in Gwt1p- or PIG-W-deficient mutant cells. Once the GPI anchor is attached to a protein, the inositol is usually deacylated in the ER. Except in human erythrocytes [42], [43], [44], almost all

Lipid remodeling and microdomain association

GPI anchoring to a protein confers a specific association with DRMs, which implies that association with a lipid-dependent structural unit has functional significance [13]. Several biochemical studies have proposed that GPI-anchored proteins are present in specialized membrane domains known as microdomains, which are sphingolipid- and sterol-rich domains in membrane [15]. However, until very recently, little was known about how GPI-anchored proteins associated with microdomains.

ER to Golgi transport of GPI-anchored proteins

Both yeast Bst1p and mammalian PGAP1 are required for the efficient transport of GPI-anchored proteins from the ER to the Golgi [35], [47]. Inositol deacylation might trigger the concentration or sorting of GPI-anchored proteins into the ER-exit site. In yeast, the transport of GPI-anchored proteins from the ER to the Golgi is substantially delayed in gup1Δ and per1Δ cells [32], [36]. On the other hand, fatty acid remodeling of GPI-anchored proteins does not affect their transport from the ER

Quality control of GPI-anchored proteins and inositol deacylation

Before exiting from the ER, proteins are monitored by a quality control system that ensures their correct folding and oligomerization. A number of chaperones and enzymes in the ER are required for proper protein folding [74]. Misfolded proteins that fail to pass the quality control checkpoint are transported back to the cytosol and are degraded by an ER-associated degradation mechanism that involves the ubiquitin–proteasome pathway [75], [76]. Post-translational modification of proteins,

Targeting of GPI-anchored proteins in yeast

Yeasts exhibit several types of cell polarity depending on their growth stage. One example is polarized growth during mating. After an alpha factor pheromone binds to a receptor, signals are transmitted inside the cell by the mitogen activating kinase cascade [80], [81]. Then, polarized growth towards the mating partner is induced and the cell changes its shape to form shmoos [82]. A mating projection is formed during the polarized growth, and proteins required for cell fusion are concentrated

Transport of proteins associated with microdomains in yeast

GPI-anchored proteins also play important roles in the targeting of membrane proteins, which change their cellular localization in response to environmental and nutritional conditions, by associating with lipid microdomains [99]. A tryptophan permease, Tat2p, is associated with DRMs and is transported to the plasma membrane at low tryptophan concentrations, whereas at high tryptophan concentrations it is polyubiquitinated by the Rsp5p ubiquitin ligase complex in early endosomes and then

Apical transport in mammalian cells

Lipid remodeling of GPI-anchored proteins is interesting in the polarized transport of GPI-anchored proteins in mammalian cells. Many GPI-anchored proteins are transported to the apical side of the plasma membrane in several types of epithelial cells, and to the axonal region of neuronal cells [104], [105], [106], although in Fischer rat thyroid cells, the majority of GPI-anchored proteins are delivered to the basolateral membrane [107]. Treatment with Fumonisin B1, which is an inhibitor of

Endocytic pathway of GPI-anchored proteins

GPI-anchored proteins are endocytosed differently from other plasma membrane proteins, but there is still controversy about endocytic pathway of GPI-anchored proteins [14], [112]. Although most endocytic pathways require at least one of the numerous dynamin isoforms for the purpose of pinching-off at the cell surface, several GPI-anchored proteins are selectively internalized through dynamin-independent pathway [113], [114]. This internalization is regulated by the small GTPase, CDC42 [114].

Perspective

In this review, we described the pathway for the lipid remodeling of GPI-anchored proteins, the genes involved in this pathway, and the functions of these genes, proteins and pathways in yeast and mammalian cells. To understand the function and regulation of the GPI anchor, it is important to consider the problem at the level of lipid-dependent organization. Lipid remodeling of GPI-anchored proteins changes their physical properties and regulates their association with microdomains both in

Note added in proof

Two articles describing CWH43 have appeared recently: M. Umemura, M. Fujita, T. Yoko-o, A. Fukamizu, Y. Jigami, Saccharomyces cerevisiae CWH43 is involved in the remodeling of the lipid moiety of GPI anchors to ceramides, Mol. Biol. Cell (2007) in press; V. Ghugtyal, C. Vionnet, C. Roubaty, A. Conzelmann, CWH43 is required for the introduction of ceramides into GPI anchors in Saccharomyces cerevisiae, Mol. Microbiol. 65 (2007) 1493–1502.

Acknowledgements

We thank Mariko Umemura, Michiyo Okamoto, Hiroto Hirayama, Takuji Oka, and Takehiko Yoko-o for their helpful discussions. This research was partially supported by a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (JSPS). M.F. was supported by a Research Fellowship for Young Scientists from the JSPS.

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Glycobiology of Yeast: Applications to Glycoprotein Expression and Remodeling
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In this article, we describe the yeast glycans and their biosynthetic pathways, focusing on the budding yeast Saccharomyces cerevisiae. The N-glycans of yeasts often consist of a large amount of saccharides called mannan. The biosynthetic pathway of N-glycans in the endoplasmic reticulum of yeast is similar to that of mammalian cells, while the pathway in the Golgi apparatus is quite different. On the other hand, the biosynthetic pathway of O-glycans seems to be specific to yeast cells. Yeast systems are useful not only for understanding the basic mechanisms of glycan synthesis but also for producing therapeutic proteins with non-antigenic glycans in humans via glycan remodeling. Protein modification by glycosylphosphatidylinositol is another post-transcriptional modification involving oligosaccharides. The biosynthetic pathway and the physiological functions of glycosylphosphatidylinositol in S. cerevisiae are described here as well as the latest findings in this field.
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Glycosylphosphatidylinositols (GPIs) are glycolipids that anchor various cell surface proteins. This post-translational modification is conserved among eukaryotes, and at least 150 cell surface proteins including receptors, adhesion molecules and hydrolytic enzymes are known to be modified by GPI in mammalian cells. GPIs are biosynthesized and transferred to proteins at the endoplasmic reticulum. More than 20 genes are involved in GPI precursor biosynthesis and transfer to proteins. Nascent GPI-anchored proteins (GPI-APs) are transported from the endoplasmic reticulum to the plasma membrane through the Golgi apparatus. The lipid and glycan moieties of GPI-anchors are remodeled during transport. Through lipid remodeling, GPI-APs become compatible to associate with dynamic membrane domains, lipid rafts. At the plasma membrane, a fraction of GPI-APs are shed by GPI-cleaving enzymes. We here describe the pathways for mammalian GPI-AP biosynthesis, modification, transport, quality control, and genes involved in the processes.
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Yeast cell wall biosynthesis and maintenance mainly depend on the GPI-anchored proteins, sorted by the ER–Golgi traffic system (1, 7, 58). PE also plays a crucial role in the regulation of this traffic system (4, 7, 44, 58). Thus, we hypothesized that the CTD-induced cell wall damage might be due to the defect in GPI-anchored protein sorting.
Cantharidin (CTD) is a potent anticancer small molecule produced by several species of blister beetle. It has been a traditional medicine for the management of warts and tumors for many decades. CTD suppresses tumor growth by inducing apoptosis, cell cycle arrest, and DNA damage and inhibits protein phosphatase 2 phosphatase activator (PP2A) and protein phosphatase 1 (PP1). CTD also alters lipid homeostasis, cell wall integrity, endocytosis, adhesion, and invasion in yeast cells. In this study, we identified additional molecular targets of CTD using a Saccharomyces cerevisiae strain that expresses a cantharidin resistance gene (CRG1), encoding a SAM-dependent methyltransferase that methylates and inactivates CTD. We found that CTD specifically affects phosphatidylethanolamine (PE)-associated functions that can be rescued by supplementing the growth media with ethanolamine (ETA). CTD also perturbed endoplasmic reticulum (ER) homeostasis and cell wall integrity by altering the sorting of glycosylphosphatidylinositol (GPI)-anchored proteins. A CTD-dependent genetic interaction profile of CRG1 revealed that the activity of the lipid phosphatase cell division control protein 1 (Cdc1) in GPI-anchor remodeling is the key target of CTD, independently of PP2A and PP1 activities. Moreover, experiments with human cells further suggested that CTD functions through a conserved mechanism in higher eukaryotes. Altogether, we conclude that CTD induces cytotoxicity by targeting Cdc1 activity in GPI-anchor remodeling in the ER.
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ReviewLipid remodeling of GPI-anchored proteins and its function

Abstract

Introduction

Section snippets

Evidence of lipid remodeling from structural analysis

Yeast BST1 and mammalian PGAP1 involved in GPI inositol deacylation

Lipid remodeling and microdomain association

ER to Golgi transport of GPI-anchored proteins

Quality control of GPI-anchored proteins and inositol deacylation

Targeting of GPI-anchored proteins in yeast

Transport of proteins associated with microdomains in yeast

Apical transport in mammalian cells

Endocytic pathway of GPI-anchored proteins

Perspective

Note added in proof

Acknowledgements

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FEBS Lett.

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J. Lipid Res.

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Curr. Opin. Microbiol.

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The structure, biosynthesis and functions of glycosylphosphatidylinositol anchors, and the contributions of trypanosome research

J. Cell Sci.

Glycosylphosphatidylinositol (GPI)-anchored proteins

Biol. Pharm. Bull.

The structure, biosynthesis and function of glycosylated phosphatidylinositols in the parasitic protozoa and higher eukaryotes

Biochem. J.

Glycosyl-phosphatidylinositol moiety that anchors Trypanosoma brucei variant surface glycoprotein to the membrane

Science

Complete structure of the glycosyl phosphatidylinositol membrane anchor of rat brain Thy-1 glycoprotein

Nature

Critical roles of glycosylphosphatidylinositol for Trypanosoma brucei

Proc. Natl. Acad. Sci. U. S. A.

Developmental abnormalities of glycosylphosphatidylinositol-anchor-deficient embryos revealed by Cre/loxP system

Lab. Invest.

Review
Lipid remodeling of GPI-anchored proteins and its function