研究者業績

内藤 裕子

ナイトウ ユウコ  (Yuko Naito)

基本情報

所属
藤田医科大学 医療科学部 放射線学科 講師
学位
博士(生命科学)(2007年5月 京都大学)
Master(Kyoto University)

J-GLOBAL ID
200901027620949683
researchmap会員ID
5000081657

論文

 17
  • Chizuru Akatsu, Yuko Naito-Matsui, Hajjaj H.M. Abdu-Allah, Akihiro Imamura, Wang Long, Hideharu Ishida, Hiromu Takematsu, Takeshi Tsubata
    Journal of Biological Chemistry 107630-107630 2024年8月  
  • Xiang Gao, Lingquan Deng, Gabrielle Stack, Hai Yu, Xi Chen, Yuko Naito-Matsui, Ajit Varki, Jorge E. Galan
    NATURE MICROBIOLOGY 2(12) 1697-1697 2017年12月  査読有り
  • Xiang Gao, Lingquan Deng, Gabrielle Stack, Hai Yu, Xi Chen, Yuko Naito-Matsui, Ajit Varki, Jorge E. Galan
    NATURE MICROBIOLOGY 2(12) 1592-1599 2017年12月  査読有り
    The evolution of virulence traits is central for the emergence or re-emergence of microbial pathogens and for their adaptation to a specific host(1-5). Typhoid toxin is an essential virulence factor of the human-adapted bacterial pathogen Salmonella Typhi(6,7), the cause of typhoid fever in humans(8-12). Typhoid toxin has a unique A(2)B(5) architecture with two covalently linked enzymatic 'A' subunits, PltA and CdtB, associated with a homopentameric 'B' subunit made up of PltB, which has binding specificity for the N-acetylneuraminic acid (Neu5Ac) sialoglycans(6,13) prominently present in humans(14). Here, we examine the functional and structural relationship between typhoid toxin and ArtAB, an evolutionarily related AB(5) toxin encoded by the broad-host Salmonella Typhimurium(15). We find that ArtA and ArtB, homologues of PltA and PltB, can form a functional complex with the typhoid toxin CdtB subunit after substitution of a single amino acid in ArtA, while ArtB can form a functional complex with wild-type PltA and CdtB. We also found that, after addition of a single-terminal Cys residue, a CdtB homologue from cytolethal distending toxin can form a functional complex with ArtA and ArtB. In line with the broad host specificity of S. Typhimurium, we found that ArtB binds human glycans, terminated in N-acetylneuraminic acid, as well as glycans terminated in N-glycolylneuraminic acid (Neu5Gc), which are expressed in most other mammals(14). The atomic structure of ArtB bound to its receptor shows the presence of an additional glycan-binding site, which broadens its binding specificity. Despite equivalent toxicity in vitro, we found that the ArtB/PltA/CdtB chimaeric toxin exhibits reduced lethality in an animal model, indicating that the host specialization of typhoid toxin has optimized its targeting mechanisms to the human host. This is a remarkable example of a toxin evolving to broaden its enzymatic activities and adapt to a specific host.
  • Yuko Naito-Matsui, Leela R. L. Davies, Hiromu Takematsu, Hsun-Hua Chou, Pam Tangvoranuntakul, Aaron F. Carlin, Andrea Verhagen, Charles J. Heyser, Seung-Wan Yoo, Biswa Choudhury, James C. Paton, Adrienne W. Paton, Nissi M. Varki, Ronald L. Schnaar, Ajit Varki
    JOURNAL OF BIOLOGICAL CHEMISTRY 292(7) 2557-2570 2017年2月  査読有り
    All vertebrate cell surfaces display a dense glycan layer often terminated with sialic acids, which have multiple functions due to their location and diverse modifications. The major sialic acids in most mammalian tissues are N-acetylneuraminic acid (Neu5Ac) and N-glycolylneuraminic acid (Neu5Gc), the latter being derived from Neu5Ac via addition of one oxygen atom at the sugar nucleotide level by CMP-Neu5Ac hydroxylase (Cmah). Contrasting with other organs that express various ratios of Neu5Ac and Neu5Gc depending on the variable expression of Cmah, Neu5Gc expression in the brain is extremely low in all vertebrates studied to date, suggesting that neural expression is detrimental to animals. However, physiological exploration of the reasons for this long term evolutionary selection has been lacking. To explore the consequences of forced expression of Neu5Gc in the brain, we have established brain-specific Cmah transgenic mice. Such Neu5Gc overexpression in the brain resulted in abnormal locomotor activity, impaired object recognition memory, and abnormal axon myelination. Brain-specific Cmah transgenic mice were also lethally sensitive to a Neu5Gc-preferring bacterial toxin, even though Neu5Gc was overexpressed only in the brain and other organs maintained endogenous Neu5Gc expression, as in wild-type mice. Therefore, the unusually strict evolutionary suppression of Neu5Gc expression in the vertebrate brain may be explained by evasion of negative effects on neural functions and by selection against pathogens.
  • Shoib Siddiqui, Flavio Schwarz, Stevan Springer, Zahra Khedri, Hai Yu, Lingquan Deng, Andrea Verhagen, Yuko Naito-Matsui, Weiping Jiang, Daniel Kim, Jie Zhou, Beibei Ding, Xi Chen, Nissi Varki, Ajit Varki
    JOURNAL OF BIOLOGICAL CHEMISTRY 292(3) 1029-+ 2017年1月  査読有り
    CD33-related Siglecs are a family of proteins widely expressed on innate immune cells. Binding of sialylated glycans or other ligands triggers signals that inhibit or activate inflammation. Immunomodulation by Siglecs has been extensively studied, but relationships between structure and functions are poorly explored. Here we present new data relating to the structure and function of Siglec-E, the major CD33-related Siglec expressed on mouse neutrophils, monocytes, macrophages, and dendritic cells. Wegenerated nine new rat monoclonal antibodies specific to mouse Siglec-E, with no cross-reactivity to Siglec-F. Although all antibodies detected Siglec-E on transfected human HEK293T cells, only two reacted with mouse bone marrow neutrophils by flow cytometry and on spleen sections by immunohistochemistry. Moreover, whereas all antibodies recognized Siglec-E-Fc on immunoblots, binding was dependent on intact disulfide bonds and N-glycans, and only two antibodies recognized native Siglec-E within spleen lysates. Thus, we further investigated the impact of Siglec-E homodimerization. Homology-based structural modeling predicted a cysteine residue (Cys-298) in position to form a disulfide bridge between two Siglec-E polypeptides. Mutagenesis of Cys-298 confirmed its role in dimerization. In keeping with the high level of 9-O-acetylation found in mice, sialoglycan array studies indicate that this modification has complex effects on recognition by Siglec-E, in relationship to the underlying structures. However, we found no differences in phosphorylation or SHP-1 recruitment between dimeric and monomeric Siglec-E expressed on HEK293A cells. Phylogenomic analyses predicted that only some human and mouse Siglecs form disulfide-linked dimers. Notably, Siglec-9,

MISC

 11

共同研究・競争的資金等の研究課題

 5

その他

 1
  • ヒト型シアル酸発現マウス(ヒトと同じくN-グリコリルノイラミン酸の発現を欠く、ヒト疾患研究用モデルマウス。)