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藤永, 由佳子 ; Fujinaga, Yukako
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Amatsu, Sho ; Matsumura, Takuhiro ; Yutani, Masahiro ; Fujinaga, Yukako ; 阿松, 翔 ; 松村, 拓大 ; 油谷, 雅広 ; 藤永, 由佳子
概要:
金沢大学医薬保健研究域医学系<br />Hemagglutinin (HA) is one of the components of botulinum neurotoxin (BoNT) complexes and it promotes
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the absorption of BoNT through the intestinal epithelium by at least two specific mechanisms: cell surface attachment by carbohydrate binding, and epithelial barrier disruption by E-cadherin binding. It is known that HA forms a three-arm structure, in which each of three protomers has three carbohydrate-binding sites and one E-cadherin-binding site. A three-arm form of HA is considered to bind to these ligands simultaneously. In the present study, we investigated how the multivalency effect of HA influences its barrier-disrupting activity. We prepared type B full-length HA (three-arm form) and mini-HA, which is a deletion mutant lacking the trimer-forming domain. Size-exclusion chromatography analysis showed that mini-HA exists as dimers (two-arm form) and monomers (one-arm form), which are then separated. We examined the multivalency effect of HA on the barrier-disrupting activity, the E-cadherin-binding activity, and the attachment activity to the basolateral cell surface. Our results showed that HA initially attaches to the basal surface of Caco-2 cells by carbohydrate binding and then moves to the lateral cell surface, where the HA acts to disrupt the epithelial barrier. Our results showed that the multivalency effect of HA enhances the barrier-disrupting activity in Caco-2 cells. We found that basal cell surface attachment and binding ability to immobilized E-cadherin were enhanced by the multivalency effect of HA. These results suggest that at least these two factors induced by the multivalency effect of HA cause the enhancement of the barrier-disrupting activity. © 2017 The Societies and John Wiley & Sons Australia, Ltd<br />Embargo Period 12 months
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藤永, 由佳子 ; FUJINAGA, Yukako
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藤永, 由佳子 ; Fujinaga, Yukako
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金沢大学医薬保健研究域医学系<br />ボツリヌス菌は、ボツリヌス神経毒素と無毒成分の複合体であるボツリヌス神経毒素複合体を産生することにより、ボツリヌス症を引き起こす。無毒成分中の HA(Hemagglutinin)は神経毒素の腸管吸収を
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著しく高 めることで神経毒素の病原性に寄与している。一方で、ha遺伝子を持たないボツリヌス菌も存在しているが、そのような菌はこれまでのところ例外なくorfx1~3 および p47遺伝子をha遺伝子の代わりに持っている。これらの遺伝子産物はHAのようにボツリヌス症の病態形成に重要であると考えられているが、それらの機能 については未知である。そこで本研究では遺伝子産物の生物活性の解析を主に行なった。<br />C. botulinum produces botulinum neurotoxin complex which is composed of botulinum neurotoxin (BoNT) and non-toxic proteins, and causes botulism. Hemagglutinin component (HA) of non-toxic proteins is known to increase the oral toxicity of BoNT by enhancing the toxin absorption across the epithelial barrier of intestine. There exist ha genes negative strains, and all of these strains have orfx1~3, and p47 genes instead of ha genes. The biological function of these genes are unknown. In this study, we investigated the biological functions of these genes mainly using recombinant proteins of these gene products.<br />研究課題/領域番号:18H02654, 研究期間(年度):2018-04-01 - 2021-03-31<br />出典：「ボツリヌス菌の病原性関連遺伝子領域に存在する機能未知遺伝子群の解析」研究成果報告書 課題番号18H02654（KAKEN：科学研究費助成事業データベース（国立情報学研究所）） （https://kaken.nii.ac.jp/report/KAKENHI-PROJECT-18H02654/18H02654seika/）を加工して作成
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