Selective export of human GPI-anchored proteins from the endoplasmic reticulum

Bonnon, Carine; Wendeler, Markus W.; Paccaud, Jean‐Pierre; Hauri, Hans‐Peter

doi:10.1242/jcs.062950

Cited by 137 publications

(144 citation statements)

References 82 publications

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“…Because of this abnormal glycan structure, we speculate that PIG-O defi cient cells might have a defect in sorting of free or protein anchored GPIs into ER exit sites. The ER exit of GPI-anchored proteins is controlled by glycan remodeling and p24 complexes act as cargo receptors for GPI anchor sorting into COPII vesicles ( 6,39,49 ). In agreement with this model, we observed a global increase in HexCer levels in the remodeling mutants PGAP1 and PGAP5 as well as for the p24 family proteins.…”

Section: Cholesterol Ester Levels Are Reduced In Cells That Do Not Sysupporting

confidence: 85%

Glycosylphosphatidylinositol anchors regulate glycosphingolipid levels

Loizides‐Mangold

David

Nesatyy

et al. 2012

Journal of Lipid Research

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This article is available online at http://www.jlr.org anchor has the core structure phosphatidylinositol (PI)-glucosamine (GlcN)-(Mannose) 3 -phosphoethanolamine (EtN-P), which is conserved among all species. After biosynthesis, the GPI anchor is attached posttranslationally to the newly generated C terminus of certain eukaryotic proteins destined for anchoring thereby tethering the protein to the membrane surface by the glycolipid moiety. GPI-anchored proteins can be released from the cell surface by phosphatidylinositol specifi c phospholipases and this cleavage event can induce major conformational changes on the GPIanchored protein itself ( 2 ).At least three organelles, the endoplasmic reticulum (ER), Golgi, and peroxisomes, are involved in the biosynthesis and remodeling of the GPI anchor. The biosynthesis is initiated on the outer side of the ER membrane. After the fi rst two reactions, the GPI anchor precursor is fl ipped and biosynthesis continues on the luminal side of the ER where the diacyl chains of phosphatidylinositol are then replaced by alkyl-acyl chains. This step is impaired in mutants of the peroxisomal alkyl phospholipid biosynthesis pathway ( 3 ).After protein attachment, the GPI anchor undergoes complex remodeling that begins in the ER with the removal of the inositol-linked acyl chain ( 4 ) and the remodeling of the GPI glycan part (5). Glycan remodeling is crucial for sorting GPI-anchored proteins into ER exit sites and their subsequent ER to Golgi transport ( 6 ). In mammalian cells, remodeling of the GPI anchor is then continued in the Golgi where the unsaturated fatty acid of the GPI anchor is replaced by a saturated fatty acid chain ( 7 ). Abstract Glycosylphosphatidylinositol (GPI) anchor biosynthesis takes place in the endoplasmic reticulum (ER).After protein attachment, the GPI anchor is transported to the Golgi where it undergoes fatty acid remodeling. The ER exit of GPI-anchored proteins is controlled by glycan remodeling and p24 complexes act as cargo receptors for GPI anchor sorting into COPII vesicles. In this study, we have characterized the lipid profi le of mammalian cell lines that have a defect in GPI anchor biosynthesis. Depending on which step of GPI anchor biosynthesis the cells were defective, we observed sphingolipid changes predominantly for very long chain monoglycosylated ceramides (HexCer). We found that the structure of the GPI anchor plays an important role in the control of HexCer levels. GPI anchordefi cient cells that generate short truncated GPI anchor intermediates showed a decrease in very long chain HexCer levels. Cells that synthesize GPI anchors but have a defect in GPI anchor remodeling in the ER have a general increase in HexCer levels. GPI-transamidase-defi cient cells that produce no GPI-anchored proteins but generate complete free GPI anchors had unchanged levels of HexCer. In contrast, sphingomyelin levels were mostly unaffected. We therefore propose a model in which the transport of very long chain ceramide from the ER to Golgi is regulated by...

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Section: Cholesterol Ester Levels Are Reduced In Cells That Do Not Sysupporting

confidence: 85%

Glycosylphosphatidylinositol anchors regulate glycosphingolipid levels

Loizides‐Mangold

David

Nesatyy

et al. 2012

Journal of Lipid Research

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“…Nevertheless, it has been recently suggested that the transport of the longer ceramides (C24), but not the shorter ones, depends on GPI ( 24 ). In addition, it has been shown that cholesterol is required for the effi cient ER export of GPI-APs, although their potential association with cholesterol is most likely not suffi cient to sort GPI-APs into specifi c ERESs and COPII vesicles ( 49 ). In contrast to yeast, GPI-AP concentration at ERESs depends on the p24 complex ( 50 ).…”

Section: Packaging Of Gpi-aps Into Er-derived Vesicles In Yeastmentioning

confidence: 99%

Trafficking of glycosylphosphatidylinositol anchored proteins from the endoplasmic reticulum to the cell surface

Muñiz

Riezman

2016

Journal of Lipid Research

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This article is available online at http://www.jlr.org vesicular traffi cking events ( 1 ). Many secretory proteins that are delivered to the cell surface, including a wide diversity of receptors, adhesion molecules, and enzymes, are attached to the external leafl et of the plasma membrane via a glycosylphosphatidylinositol (GPI) anchor ( 2 ). The core structure of the GPI anchor precursor is largely conserved in evolution and consists of a phospholipid moiety (acylphosphatidylinositol) with a glycan backbone [Man4-(EtNP)Man3-(EtNP)Man2-(EtNP)Man1-GlcN], where EtNP is a side-branch ethanolamine-phosphate, Man is mannose (the numbers represent the positions of the Man in the anchor), and GlcN is glucosamine). Once the GPI anchor precursor has been made by a series of sequential reactions at the ER membrane, it is then attached en bloc in the ER lumen by a GPI-transamidase complex to newly synthesized proteins containing a GPI attachment signal sequence at their C terminus. Immediately after attachment to the protein, the structure of the lipid and glycan parts of the GPI anchor are modifi ed by several remodeling enzymes ( 3 ). This remodeling process converts the GPI anchor into a transport signal that actively promotes the ER export of GPI-anchored proteins (GPI-APs) to the Golgi apparatus, from where they are subsequently routed to their functional site of residence, the plasma membrane.The presence of the GPI anchor confers to GPI-APs a unique mode of membrane association within the lumen of secretory organelles that leads them to be transported The eukaryotic secretory pathway is responsible for the synthesis and delivery of correctly assembled proteins from the endoplasmic reticulum (ER) to their fi nal functional destination, the extracellular media, the plasma membrane, or the endocytic/secretory membrane system. The vast majority of proteins are transported by a series of specifi c Abstract In eukaryotes, many cell surface proteins are attached to the plasma membrane via a glycolipid glycosylphosphatidylinositol (GPI) anchor. GPI-anchored proteins (GPI-APs) receive the GPI anchor as a conserved posttranslational modifi cation in the lumen of the endoplasmic reticulum (ER). After anchor attachment, the GPI anchor is structurally remodeled to function as a transport signal that actively triggers the delivery of GPI-APs from the ER This work was supported by grants

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“…In wild-type cells, GPI-anchored reporter proteins were immunoprecipitated with the p24 family proteins, p23 (Tmed10) and p24 (Tmed2), whereas the binding of a GPIanchored reporter to p23 and p24 was significantly decreased in PGAP1 and PGAP5 mutant cells (73). It also has been shown that knockdown of p23 and p24 caused delayed transport of GPI-anchored proteins from the ER to the Golgi in HeLa and CHO cells (74,75). In addition, sorting of GPIanchored proteins into the ER-exit sites was impaired in p23-knockdown cells.…”

Section: Er-to-golgi Transport Of Gpi-anchored Proteinsmentioning

confidence: 99%

“…There are three Sec24 paralogs (Sec24p, Sfb2p, Lst1p) in yeast and four Sec24 paralogs (Sec24A, B, C, D) in mammals. It has been reported that yeast Lst1p and mammalian Sec24C/D recognize the transport signal of p24 family proteins (65,74). Because the transport of GPI-anchored proteins was also delayed by deletion of yeast LST1 or knockdown of mammalian Sec24C/D, it seems that GPI-anchored proteins are indirectly recognized and transported by COPII vesicles via p24 family proteins (74,79).…”

Section: Er-to-golgi Transport Of Gpi-anchored Proteinsmentioning

confidence: 99%

“…It has been reported that yeast Lst1p and mammalian Sec24C/D recognize the transport signal of p24 family proteins (65,74). Because the transport of GPI-anchored proteins was also delayed by deletion of yeast LST1 or knockdown of mammalian Sec24C/D, it seems that GPI-anchored proteins are indirectly recognized and transported by COPII vesicles via p24 family proteins (74,79). Analysis in yeast has demonstrated that although the COPII component, Sec13p, is indispensable for survival, sec13∆ cells could survive when the BST1 gene, which encodes GPI-inositol deacylase, or the EMP24 and ERV25 genes, which encode p24 family proteins, were mutated (80).…”

Section: Er-to-golgi Transport Of Gpi-anchored Proteinsmentioning

confidence: 99%

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Potential Roles of GPI-Anchor Remodeling in Protein Trafficking and Raft Association in Mammalian Cells

Fujita

2012

TIGG

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Post-translational modification of proteins with glycosylphosphatidylinositol (GPI) is mediated by a mechanism that is conserved in all eukaryotes. GPI-anchored proteins are characterized by their association with specialized membrane domains called "lipid rafts," and the GPI-anchors are thought to regulate their intracellular trafficking pathways. These characteristics are regulated by the structural properties of GPI-anchors, remodeling enzymes and recognition molecules. The biogenesis of GPI-anchored proteins occurs in the ER, following which they are transported to the plasma membrane via the Golgi apparatus. During transport, the structures of the GPI-anchors are remodeled. In this minireview, the structural remodeling of mammalian GPIanchors and regulation of the transport and localization of GPI-anchored proteins are described.

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Selective export of human GPI-anchored proteins from the endoplasmic reticulum

Cited by 137 publications

References 82 publications

Glycosylphosphatidylinositol anchors regulate glycosphingolipid levels

Glycosylphosphatidylinositol anchors regulate glycosphingolipid levels

Trafficking of glycosylphosphatidylinositol anchored proteins from the endoplasmic reticulum to the cell surface

Potential Roles of GPI-Anchor Remodeling in Protein Trafficking and Raft Association in Mammalian Cells

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