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Immunoglycobiology

TEL +81-6-6879-8329

FAX +81-6-6875-5233

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Overview

We have these major projects, "GPI" as a Key Word.

I. GPI-anchor biosynthesis and transport/remodeling of GPI-anchored proteins (GPI-APs)

GPI (glycosylphosphatidylinositol)-anchor is a glycolipid which acts as a lipid anchor for various plasma-membrane proteins. GPI-APs play important roles in the host's self-defense, intercellular signal transduction, and other important processes. PIG genes (Phosphatidyl Inositol Glycan) are involved in the biosynthesis of GPI-anchor and the binding to proteins in the ER. PGAP genes (Post GPI-attachment to Proteins) are involved in later processes, glycan and lipid remodeling of GPI-anchor, which enables GPI-APs to be localized on the rafts. (*) In the mutants which are defective in lipid remodeling, GPI-APs cannot be efficiently transported and localized on the rafts. We are to investigate further on the biological meaning of GPI using these mutants. （*） Fujita, M. et al. (2009) Cell, 139:352-365.
（*） Fujita, M. et al. (2009) Cell, 139:352-365. 

Fig.1 GPI-anchored proteins

II. Pathogenesisof PNH (Paroxysmal nocturnal hemoglobinuria)

PNH is an acquired hematopoietic stem cell disorder in which clonal cells defective in GPI biosynthesis are expanded. Abnormal erythrocytes lack CD59 and DAF/CD55, widely distributed GPI anchored proteins that inhibit activation of complement on the host cell surface, are very sensitive to complement and are lysed during infections and other events. We have reported that the responsible gene is PIG-A, the catalytic subunit of the first enzyme in GPI biosynthesis. We are proposing 3step hypothesis. Step 1 involves the generation of a GPI-deficient hematopoietic stem cell by somatic mutation of the PIG-A gene. Step 2 involves the immunological selection of GPI-deficient hematopoietic stem cells. At this step, GPI-deficient cells survive and proliferate much more frequently than usual to compensate for anemia. Elevated proliferation would increase the chance of additional genetic mutations. Step 3 involves the generation of a subclone bearing the growth phenotype. （*） We are to identify the cytotoxic cells and their targets, a GPI-AP which plays a role in immunological selection and an additional genetic mutation.
（*） N. Inoue et al (2006) Blood, 108:4232-4236
（**） A. M. Almeida (2007) N Eng J Med, 356:1641-1647

Fig.2 Pathogenesis of PNH

Principal Investigator

Taroh Kinoshita Professor

Research field

Immunology, Biochemistry

Education history

1974 Faculty of Agriculture, University of Tokyo, Tokyo, Japan (B.Agr. 1974)
1977 Graduate School of Agricultural Sciences, University of Tokyo (M.Agr. 1977)
1981 Graduate School, Osaka University Medical School, Osaka Japan (Ph.D. 1981)

Research and career history

1981 Postdoctoral Fellow, supported by a postdoctoral fellowship from the Japan Society for the Promotion of Science (-1982)
1982 Research Associate, Department of Bacteriology, Osaka University Medical School, Osaka, Japan
1982 Postdoctoral Research Associate, Department of Pathology, New York University School of Medicine, New York NY (-1985)
1985 Research Associate, Department of Bacteriology, Osaka University Medical School (-1988)
1988 Assistant Professor, Department of Bacteriology, Osaka University Medical School (-1990)
1990- Professor, Department of Immunoregulation, Research Institute for Microbial Diseases, Osaka University (-present)
1998 Director, Genome Information Research Center, Osaka University (-2003)
2003 Director, Research Institute for Microbial Diseases, Osaka University (-2007)
2007- Professor, Laboratory of Immunoglycobiology, WPI Immunology Frontier Research Center, Osaka University
2017- Endowed Chair Professor, Yabumoto Department of Intractable Disease Research, Research Institute for Microbial Diseases, Osaka University

Prize

2001 The 19th Osaka Science Prize
2010 Commendation for Science and Technology by MEXT （Prizes for Science and Technology)
2015 IGO　Award (International Glycoconjugate Organization)
2017 Takeda Prize for Medical Science
2017 4th JSI Human Immunology Research Award
2017 The Emperor's Purple Ribbon Medal
2021 Hayaishi Memorial Prize 2021
2022 The Toyoichi Ohtawara Award 2021
2023 Karl Meyer Lectureship Award

Members

  • Taroh Kinoshita Professor
    tkinoshibiken.osaka-u.ac.jp

  • Yoshiko Murakami　Professor
    yoshikohbiken.osaka-u.ac.jp

Achievements

Publications

  • Chiyonobu, T., N. Inoue, M. Morimoto, T. Kinoshita and Y. Murakami. 2014. Glycosylphosphatidylinositol (GPI) anchor deficiency caused by mutations in PIGW is associated with West syndrome and hyperphosphatasia with mental retardation syndrome. J. Med. Genet., 51:203-207.
  • Howard, M. F., Y. Murakami, A. T. Pagnamenta, C. Daumer-Haas, B. Fischer, J. Hecht, D. A. Keays, S. J. L. Knight, U. Kölsch, U. Krüger, S. Leiz, Y. Maeda, D. Mitchell, S. Mundlos, J. A. Phillips III, P. N. Robinson, U. Kini, J. C. Taylor, D. Horn, T. Kinoshita, P. M. Krawitz. 2014. Mutations in PGAP3 impair GPI-anchor maturation causing a new subtype of hyperphosphatasia with intellectual disability. Am. J. Hum. Genet., 94:278-287.
  • Nishimura, J., M. Yamamoto, S. Hayashi, K. Ohyashiki, K. Ando, A. L. Brodsky, H. Noji, K. Kitamura, T. Eto, T. Takahashi, M. Masuko, T. Matsumoto, Y. Wano, T. Shichishima, H. Shibayama, M. Hase, L. Li, K. Johnson, A. Lazarowski, P. Tamburini, J. Inazawa, T. Kinoshita and Y. Kanakura. 2014. Genetic variants in C5 and poor response to eculizumab. N. Eng. J. Med., 370:632-639.
  • Fujiwara, I., Y. Murakami, T. Niihori, J. Kanno, A. Hakoda, O. Sakamoto, N. Okamoto, R. Funayama, T. Nagashima, K. Nakayama, T. Kinoshita, S. Kure, Y. Matsubara, and Y. Aoki. Mutations in PIGL in a patient with Mabry syndrome. 2015. Am J Med Genet, 167A:777-785.
  • Kato, M., H. Saitsu, Y. Murakami, K. Kikuchi, S. Watanabe, M. Iai, K. Miya, R. Matsuura, R. Takayama, C. Ohba, M. Nakashima, Y. Tsurusaki, N. Miyake, S. Hamano, H. Osaka, K. Hayasaka, T. Kinoshita and N. Matsumoto. 2014. PIGA mutations cause early-onset epileptic encephalopathies and distinctive features. Neurology, 82:1587-1596.
  • Murakami, Y., H. Tawamie, Y. Maeda, C. Buttner, R. Buchert, F. Radwan, S. Schaffer, H. Sticht, M. Aigner, A. Reis, T. Kinoshita and R. A. Jamra. 2014. Null mutation in PGAP1 impairs GPI-anchor maturation in patients with intellectual disability and encephalopathy. PLoS Genet., 10(5):e1004320.
  • Theiler, R., M. Fujita, M. Nagae, Y. Yamaguchi, Y. Maeda and T. Kinoshita. 2014. The alpha helical region in p24γ2 subunit of p24 cargo receptor is pivotal for the recognition and transport of glycosylphosphatidylinositol-anchored proteins. J Biol. Chem., 289:16835-16843.
  • Stokes, M., Y. Murakami, Y. Maeda, T. Kinoshita and Y. S. Morita. 2014. New insights to the functions of PIGF, a protein involved in the ethanolamine phosphate transfer steps of glycosylphosphatidylinositol biosynthesis. Biochem. J., 463:249-256.
  • Bosch, D.G.M, F.N. Boonstra, T. Kinoshita, J. de Ligt, F.P.M. Cremers, J.R. Lupski, Y. Murakami and B.B.A. de Vries. 2015. Cerebral visual impairment and intellectual disability caused by PGAP1 mutations. Eur. J. Hum. Genet., 23:1689-1693.
  • Bosch, D.G.M, F.N. Boonstra, T. Kinoshita, J. de Ligt, F.P.M. Cremers, J.R. Lupski, Y. Murakami and B.B.A. de Vries. 2015. Cerebral visual impairment and intellectual disability caused by PGAP1 mutations. Eur. J. Hum. Genet., 23:1689-1693.
  • Ilkovski, B. A., T. Pagnamenta, G. L. O’Grady, T. Kinoshita, M. F. Howard, M. Lek, B. Thomas, A. Turner, J. Christodoulou, D. Sillence, S. J.L. Knight, N. Popitsch, D. A. Keays, C. Anzilotti, A. Goriely, L. B. Waddell, F. Brilot, K. N. North, N. Kanzawa, D. G. MacArthur, J. C. Taylor, U. Kini1, Y. Murakami and N. F. Clarke. 2015. Mutations in PIGY: expanding the phenotype of inherited glycosylphosphatidylinositol deficiencies. Hum. Mol. Genet., 24:6146-6159. 
  • Makrythanasis P., M. Kato, M. Zaki, H. Saitsu, K. Nakamura, F. Santoni, S. Miyatake, M. Nakashima, M. Y. Issa, M. Guipponi, A. Letourneau, C. Logan, N. Roberts, D. A. Parry, C. A. Johnson, N. Matsumoto, H. Hamamy, E. Sheridan, T. Kinoshita, S. E. Antonarakis and Y. Murakami. 2016. Pathogenic variants in PIGG cause intellectual disability with seizures and hypotonia. Am. J. Hum. Genet., 98:615-626.
  • Knaus, A., T. Awaya, I. Helbig, Z. Afawi, M. Pendziwiat, J. Abu-Rachma, M. Thompson, D. Cole, S. Skinner, F. Annese, N. Canham, M. Schweiger, P. N. Robinson, S. Mundlos, T. Kinoshita, A. Munnich, Y. Murakami, D. Horn and P. Krawitz. 2016. Rare non-coding mutations extend the mutational spectrum in the PGAP3 subtype of Hyperphosphatasia with Mental Retardation Syndrome. Hum. Mutat., 37:737-744.
  • Nagae, M., T. Hirata, K. Morita-Matsumoto, R. Theiler, M. Fujita, T. Kinoshita and Y. Yamaguchi. 2016. 3D structure and interaction of p24 and p24 Golgi dynamics domains: implication for p24 complex formation and cargo transport. J. Mol. Biol., 428:4087-4099.
  • Hogrebe, M., Y. Murakami, M. Wild, M. Ahlmann, S. Biskup, K. Hoertnagel, M. Grueneberg, J. Reunert, T. Linden, T. Kinoshita and T. Marquardt. 2016. A novel mutation in PIGW causes glycosylphosphatidylinositol deficiency without hyperphosphatasia. Am. J. Med. Genet. A, 170:3319-3322.
  • Edvardson, S., Y. Murakami, T. T. M. Nguyen, M. Shahrour, A. St-Denis, A. Shaag, N. Damseh, S. Chiang Cern Cher, F. Le Deist, Y. Bryceson, B. Abu-Libdeh, P. M. Campeau, T. Kinoshita and O. Elpeleg. 2016. Mutations in the phosphatidylinositol glycan C (PIGC) gene are associated with epilepsy and intellectual disability. J. Med. Genet., 54:196-201.
  • Lee, G-H., M. Fujita, K. Takaoka, Y. Murakami, Y. Fujihara, N. Kanzawa, K. Murakami, E. Kajikawa, Y. Takada, K. Saito, M. Ikawa, H. Hamada, Y. Maeda and T. Kinoshita. 2016. A GPI processing phospholipase A2, PGAP6, modulates Nodal signaling in embryos by shedding CRIPTO. J. Cell Biol., 215:705-718.
  • Kolicheski, A. L., G. S. Johnson, T. Mhlanga-Mutangadura, J. F. Taylor, R. D. Schnabel, T. Kinoshita, Y. Murakami, D. P. O’Brien. 2016. A homozygous PIGN missense　mutation in soft coated wheatenterriers with a canine paroxysmal non-kinesigenic dyskinesia. Neurogenetics, in press.
  • Pagnamenta, A. T. , M. F. Howard, J. M. Taylor, V. Miller, D. S. Johnson, S. Tadros, S. Mansour, I. K. Temple, R. Firth, E. Rosser, R. Harrison, B. Kerr, N. Popitsch, The Deciphering Developmental Disorders Study, Y. Murakami, T. Kinoshita, J. C. Taylor, U. Kini. 2016. Analysis of exome data for 4293 trios suggests GPI-anchor biogenesis defects are a rare cause of developmental disorders. Eur. J. Hum. Genet., in press.
  • Ihara, S., S. Nakayama, Y. Murakami, E. Suzuki, M. Asakawa, T. Kinoshita and H. Sawa. 2017. PIGN prevents protein aggregation in the endoplasmic reticulum independently of its function in the GPI synthesis. J. Cell Sci., 130:602-613.
  • Nagae, M., D. Liebschner, Y. Yamada, K. Morita-Matsumoto, N. Matsugaki, T. Senda, M. Fujita, T. Kinoshita and Y. Yamaguchi. 2017. Crystallographic analysis of murine p242 Golgi Dynamics (GOLD) domain. Proteins: Structure, Function and Bioinformatics, in press.
  • Johnstone, D. L., T. Tuyet-Mai Nguyen*, Y. Murakami*, K. D. Kernohan, M. Tétreault, C. Goldsmith, A. Doja, J. D. Wagner, L. Huang, T. Hartley, A. St-Denis, F. le Deist, J. Majewski, D. E. Bulman, Care4Rare Canada Consortium, T. Kinoshita, D. A. Dyment, K. M. Boycott and P. M. Campeau. 2017. Compound heterozygous mutations in the gene PIGP are associated with early infantile epileptic encephalopathy. Hum. Mol. Genet., in press.
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