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Biosynthesis and Deficiencies of Glycosylphosphatidylinositol

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Biosynthesis and Deficiencies of Glycosylphosphatidylinositol 130 Proc. Jpn. Acad., Ser. B 90 (2014) [Vol. 90, Review Biosynthesis and deficiencies of glycosylphosphatidylinositol † By Taroh KINOSHITA*1, (Communicated by Kunihiko SUZUKI, M.J.A.) Abstract: At least 150 different human proteins are anchored to the outer leaflet of the plasma membrane via glycosylphosphatidylinositol (GPI). GPI preassembled in the endoplasmic reticulum is attached to the protein’s carboxyl-terminus as a post-translational modification by GPI transamidase. Twenty-two PIG (for Phosphatidyl Inositol Glycan) genes are involved in the biosynthesis and protein-attachment of GPI. After attachment to proteins, both lipid and glycan moieties of GPI are structurally remodeled in the endoplasmic reticulum and Golgi apparatus. Four PGAP (for Post GPI Attachment to Proteins) genes are involved in the remodeling of GPI. GPI- anchor deficiencies caused by somatic and germline mutations in the PIG and PGAP genes have been found and characterized. The characteristics of the 26 PIG and PGAP genes and the GPI deficiencies caused by mutations in these genes are reviewed. Keywords: glycosylphosphatidylinositol, glycolipid, post-translational modification, somatic mutation, germline mutation, deficiency glycolipid membrane anchors. GPI-APs are typical Introduction raft-associated proteins and tend to form homo- At least 150 different human proteins are post- dimers.3),4) GPI-APs can be released from the translationally modified by glycosylphosphatidylino- cell after cleavage by GPI-cleaving enzymes or sitol (GPI) at the carboxyl (C)-terminus.1),2) These GPIases.5)–8) These characteristics are critical for proteins are expressed on the cell surface by being the functions of individual GPI-APs and for embryo- anchored to the outer leaflet of the plasma membrane genesis, neurogenesis, fertilization, and the immune via the phosphatidylinositol (PI) moiety and termed system.5),8)–11) GPI-anchored proteins (GPI-APs). While the func- Protein-bound mammalian GPI-anchors have tions of GPI-APs are various, including hydrolytic a core backbone, which can be modified by side enzymes, adhesion molecules, receptors, protease branches (Fig. 1). The structure of the core back- inhibitors, and complement regulatory proteins, they bone is EtNP-6Man,1-2Man,1-6Man,1-4GlcN,1- share similar characteristics based on their common 6myoInositol-phospholipid (where EtNP is ethanol- amine phosphate, Man is mannose, and GlcN is , *1 WPI Immunology Frontier Research Center and Research glucosamine). EtNP linked to Man3, the 1-2-linked Institute for Microbial Diseases, Osaka University, Osaka, Japan. Man, makes an amide-bond with the C-terminus of † Correspondence should be addressed: T. Kinoshita, WPI the protein. 1-Alkyl-2-acyl PI is the major form of Immunology Frontier Research Center and Research Institute for inositol phospholipid in protein-bound mammalian Microbial Diseases, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan (e-mail: [email protected]). GPI-APs and diacyl PI is a minor form. Mammalian Abbreviations: C: carboxyl; CHO: Chinese hamster ovary; GPI-APs usually have two saturated fatty chains, Dol-P-Man: dolichol-phosphate mannose; EBV: Epstein-Barr with a small fraction containing one unsaturated virus; ER: endoplasmic reticulum; EtNP: ethanolamine phosphate; bond in an sn1-linked chain. The sn2-linked fatty GalNAc: N-acetylgalactosamine; GlcN: glucosamine; GlcNAc: N- acetylglucosamine; GPI: glycosylphosphatidylinositol; GPI-AP: acid is usually stearic acid (C18:0), while the sn1- GPI-anchored protein; GPI-GnT: GPI-GlcNAc transferase; linked chain has 18 or 16 carbons. HPMRS: hyperphosphatasia with mental retardation syndrome; Mammalian GPI-APs have a common EtNP fi IGD: inherited GPI de ciency; Man: mannose; MCAHS: multiple side branch linked to the 2-position of Man1, the ,1- congenital anomalies with hypotonia and seizures; N: amino; PI: phosphatidylinositol; PI-PLC: PI-specific phospholipase C; PNH: 4-linked Man. Some of the mammalian GPI-APs paroxysmal nocturnal hemoglobinuria. have a fourth Man as a side branch that is ,1-2- doi: 10.2183/pjab.90.130 ©2014 The Japan Academy No. 4] Biosynthesis and deficiencies of glycosylphosphatidylinositol 131 malian GPI (Figs. 2 and 4). For the last two decades, my laboratory has been working on the identification P EtN Ethanolamine phosphate and characterization of these genes, and clarification Protein of the GPI deficiencies caused by somatic and Mannose germline mutations in these genes. In this article, I review these genes and GPI deficiencies. Glucosamine EtN P PIG (for Phosphatidyl Inositol Glycan) P Alkyl,acyl or diacyl PI genes involved in the biosynthesis and transfer of GPI N-acetylgalactosamine P EtN 1. PIGA (for Phosphatidyl Inositol Glycan complementation class A) gene. Robert Hyman Galactose P established several mouse T-lymphoma cell lines fi N-acetylneuraminic acid defective in surface expression of Thy-1 and classi ed them into complementation classes by means of Plasma membrane somatic cell hybridization.14) After Thy-1 was iden- fi Fig. 1. Structure of mammalian GPI-APs. The structure of ti ed as a GPI-AP, several researchers studied the core backbone is EtNP-6Man,1-2Man,1-6Man,1-4GlcN,1- biosynthetic defects in the mutant cell lines and 6myoInositol-phospholipid. The EtNP linked to Man3, the ,1- found that classes A, C, and H were defective in the 2 linked Man, makes an amide-bond with the C-terminus. The first step of GPI biosynthesis.15),16) These findings , EtNP side-branch linked to Man1, the 1-4 linked Man, is indicated that at least three genes were involved in common among proteins whereas the Man side-branch that is fi ,1-2 linked to Man3, and GalNAc side-branch that is O1-4 linked the rst step, transfer of N-acetylglucosamine to Man1 are found in some of the GPI-APs. The GalNAc side- (GlcNAc) from UDP-GlcNAc to PI generating the branch can be further modified by galactose and sialic acid. first intermediate GlcNAc-PI. We found that JY5 cells, GPI-AP-deficient cells derived from the human B-lymphoblastoid cell line JY, were defective in the linked to Man3. These side branches are added to first step and belonged to class A.17) Since the JY cell GPI-precursors during biosynthesis in the endoplas- line was transformed by Epstein-Barr virus (EBV) mic reticulum (ER) before attachment to proteins. and expressed EBNA1 nuclear antigen, we estab- The third known side branch is N-acetylgalactos- lished an expression cloning system in which JY5 amine (GalNAc), which is O1-4-linked to Man1. This cells were transfected with an EBV vector-based GalNAc can be further modified by galactose and cDNA library. In this system, cells that regained sialic acid (Fig. 1).12) Although the enzymes required surface expression of GPI-APs were collected by cell for making the GalNAc-containing side branches sorting, and episomal plasmids were rescued and remain to be identified, these modifications are likely retransfected into JY5 cells. This process was to occur after attachment to proteins and after repeated three times and finally a PIGA cDNA that transport to the Golgi apparatus. could restore surface GPI-AP expression on JY5 cells GPI precursors are synthesized in the ER and was cloned.17) transferred en bloc to proteins that bear a GPI- The PIG-A protein encoded by the PIGA cDNA attachment signal sequence at the C-terminus consists of 484 amino acids, has one transmembrane (Fig. 2). Transfer of GPI to proteins is mediated by domain near the C-terminus, and is expressed in GPI-transamidase, which recognizes the GPI-attach- the ER. The amino (N)-terminal large hydrophilic ment signal sequence and replaces it with the GPI- portion resides on the cytoplasmic side and a short precursor by a transamidation reaction (Fig. 3).1),13) hydrophilic portion resides in the ER lumen.18) PIG- After protein-attachment, GPI-APs are structurally A is a catalytic subunit of GPI-GlcNAc transferase remodeled at both lipid and glycan parts of GPI, (GPI-GnT).19) recruited into COPII-coated transport vesicles at 2. PIGH gene. Kamitani and colleagues found the ER exit sites, transported to the Golgi, further that murine Ltk- cells were defective in the first step modified in the lipid part of GPI, and finally of GPI biosynthesis and belonged to the class H expressed on the cell surface (Fig. 4). complementation group. They used an expression At least 26 genes are involved in the biosyn- cloning system involving a cDNA library generated in thesis, protein-attachment, and remodeling of mam- a polyoma virus-based vector and identified a PIGH 132 T. KINOSHITA [Vol. 90, PIG-A PIG-K PIG-C PIG-F PIG-F PIG-N GPAA1 PIG-H PIG-M PIG-O PIG-G PIG-S PIG-L PIG-W PIG-V PIG-P PIG-X PIG-B PIG-T PIG-Q PIG-U PIG-Y EtN EtN EtN EtN DPM2 P P P P P EtN P EtN P EtN P EtN P EtN P EtN P EtN P EtN Lumen P P P P P P P P P P P ER PM P P P (4) (5) (6) (7) (8) (9) (10) (11) (3) PI (1) (2) P EtN Ethanolamine phosphate N-acetylglucosamine Diacyl glycerol Saturated chain Glucosamine Alkyl,acyl or diacyl Unsaturated chain Mannose glycerol Fig. 2. Biosynthesis and attachment to proteins of GPI. GPI precursor is biosynthesized in the ER by at least 11 stepwise reactions and en bloc transferred to the C-terminus of proteins. GlcN-PI flips from the cytoplasmic side to the luminal side (step 3). Lipid structure changes from diacyl PI to a mixture of 1-alkyl,2-acyl PI, major form, and diacyl PI, minor form in GlcN-(acyl)PI (step 5). Lumen GPI-AP Precursor GPI protein N transamidase N-terminal ω signal ω+1 ω+2 peptide P P P ER N GPI attachment signal peptide C Fig.
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