九州大学 研究者情報
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白銀 勇太(しろがね ゆうた) データ更新日:2021.12.02

助教 /  医学研究院 基礎医学部門 病態制御学講座


主な研究テーマ
ムンプスウイルスは急性耳下腺炎(おたふく風邪)の原因ウイルスです。しかしながらなぜ唾液腺を含む腺組織を好んでウイルスが増殖するのかについては何も分かっていません。私たちはムンプスウイルスの宿主因子としてLAMPファミリー分子が重要であることを発見しました(Ueo et al., 2020, Journal of Virology)。LAMPファミリー分子はムンプスウイルスの膜融合タンパク質の開裂をサポートする機能を持っています。この分子は腺組織にも発現を認めるため、「なぜムンプスウイルスがおたふく風邪を引き起こすのか」の鍵になり得る分子です。現在私たちはこのLAMPファミリー分子について、研究を進めています。
キーワード:ムンプスウイルス、急性耳下腺炎、LAMPファミリー、膜融合
2015.04~2025.05.
麻疹ウイルスは麻疹の病原体ですが、まれに脳内に感染し難治性の亜急性硬化性全脳炎を引き起こします。
とはいっても、もともと麻疹ウイルスは脳内で増殖することができないウイルスです。
大変興味深いことですが、麻疹ウイルスは脳内で「進化」して病気を引き起こすことが解明されつつあります。
このようなウイルスの進化に関する研究の他に、異種のウイルス同士がどのように影響を与え合う、すなわち「相互作用」するのか、そのメカニズムの研究も進めています。
基礎的なウイルス学の研究を進めることで、最終的に治療など人類の福祉の向上に貢献したいと思っています。
キーワード:麻疹ウイルス、亜急性硬化性全脳炎、ムンプスウイルス、進化、相互作用
2018.04.
研究業績
主要著書
主要原著論文
1. Yinghong Xiao, Peter V. Lidsky, Yuta Shirogane, Ranen Aviner, Chien-Ting Wu, Weiyi Li, Weihao Zheng, Dale Talbot, Adam Catching, Gilad Doitsh, Weiheng Su, Colby E. Gekko, Arabinda Nayak, Joel D. Ernst, Leonid Brodsky, Elia Brodsky, Elsa Rousseau, Sara Capponi, Simone Bianco, Robert Nakamura, Peter K. Jackson, Judith Frydman, Raul Andino, A defective viral genome strategy elicits broad protective immunity against respiratory viruses, Cell, 10.1016/j.cell.2021.11.023, 2021.11.
2. Ryuichi Takemoto, Tateki Suzuki, Takao Hashiguchi, Yusuke Yanagi, Yuta Shirogane, Short-stalk isoforms of CADM1 and CADM2 trigger neuropathogenic measles virus-mediated membrane fusion by interacting with the viral hemagglutinin, Journal of Virology, 10.1128/JVI.01949-21, 2021.11, Measles virus (MeV), an enveloped RNA virus in the family Paramyxoviridae, usually causes acute febrile illness with skin rash, but in rare cases persists in the brain, causing a progressive neurological disorder, subacute sclerosing panencephalitis (SSPE). MeV bears two envelope glycoproteins, the hemagglutinin (H) and fusion (F) proteins. The H protein possesses a head domain that initially mediates receptor binding and a stalk domain that subsequently transmits the fusion-triggering signal to the F protein. We have recently shown that cell adhesion molecule 1 (CADM1, also known as IGSF4A, Necl-2, SynCAM1) and CADM2 (also known as IGSF4D, Necl-3, SynCAM2) are host factors enabling cell-cell membrane fusion mediated by hyperfusogenic F proteins of neuropathogenic MeVs as well as MeV spread between neurons lacking the known receptors. CADM1 and CADM2 interact in cis with the H protein on the same cell membrane, triggering hyperfusogenic F protein-mediated membrane fusion. Multiple isoforms of CADM1 and CADM2 containing various lengths of their stalk regions are generated by alternative splicing. Here we show that only short-stalk isoforms of CADM1 and CADM2 predominantly expressed in the brain induce hyperfusogenic F protein-mediated membrane fusion. While the known receptors interact in trans with the H protein through its head domain, these isoforms can interact in cis even with the H protein lacking the head domain and trigger membrane fusion, presumably through its stalk domain. Thus, our results unveil a new mechanism of viral fusion triggering by host factors..
3. Yuta Shirogane, Ryuichi Takemoto, Tateki Suzuki, Tomonori Kameda, Kinichi Nakashima, Takao Hashiguchi, Yusuke Yanagi, CADM1 and CADM2 trigger neuropathogenic measles virus-mediated membrane fusion by acting in cis, Journal of Virology, 10.1128/JVI.00528-21, 2021.04.
4. Yuta Shirogane, Bert L. Semler, Elsa Rousseau, Jakub Voznica, Yinghong Xiao, Weiheng Su, Adam Catching, Zachary J. Whitfield, Igor M. Rouzine, Simone Bianco, Raul Andino, Experimental and mathematical insights on the interactions between poliovirus and a defective interfering genome, PLOS Pathogens, 10.1371/journal.ppat.1009277, 2021.09, During replication, RNA viruses accumulate genome alterations, such as mutations and deletions. The interactions between individual variants can determine the fitness of the virus population and, thus, the outcome of infection. To investigate the effects of defective interfering genomes (DI) on wild-type (WT) poliovirus replication, we developed an ordinary differential equation model. We experimentally determined virus and DI replication during co-infection, and use these data to infer model parameters. Our model predicts, and our experimental measurements confirm, that DI replication and encapsidation are the most important determinants for the outcome of the competition. WT replication inversely correlates with DI replication. Our model predicts that genome replication and effective DI genome encapsidation are critical to effectively inhibit WT production, but an equilibrium can be established which enables WT to replicate, albeit to reduce levels..
5. Ayako Ueo, Marie Kubota, Yuta Shirogane, Shinji Ohno, Takao Hashiguchi, Yusuke Yanagi, Lysosome-associated membrane proteins support the furin-mediated processing of the mumps virus fusion protein, Journal of Virology, 2020.06, Mumps virus (MuV), an enveloped RNA virus of the Paramyxoviridae family and the causative agent of mumps, affects the salivary glands and other glandular tissues as well as the central nervous system. The virus enters the cell by inducing the fusion of its envelope with the plasma membrane of the target cell. Membrane fusion is mediated by MuV envelope proteins: the hemagglutininneuraminidase and fusion (F) protein. Cleavage of the MuV F protein (MuV-F) into two subunits by the cellular protease furin is a prerequisite for fusion and virus infectivity. Here, we show that 293T (a derivative of HEK293) cells do not produce syncytia upon expression of MuV envelope proteins or MuV infection. This failure is caused by the inefficient MuV-F cleavage despite the presence of functional furin in 293T cells. An expression cloning strategy revealed that overexpression of lysosome-associated membrane proteins (LAMPs) confers on 293T cells the ability to produce syncytia upon expression of MuV envelope proteins. The LAMP family comprises the ubiquitously expressed LAMP1 and LAMP2, the interferon-stimulated gene product LAMP3, and the cell type-specific proteins. The expression level of the LAMP3 gene, but not of LAMP1 and LAMP2 genes, differed markedly between 293T and HEK293 cells. Overexpression of LAMP1, LAMP2, or LAMP3 allowed 293T cells to process MuV-F efficiently. Furthermore, these LAMPs were found to interact with both MuV-F and furin. Our results indicate that LAMPs support the furin-mediated cleavage of MuV-F and that, among them, LAMP3 may be critical for the process, at least in certain cells. IMPORTANCE The cellular protease furin mediates proteolytic cleavage of many host and pathogen proteins and plays an important role in viral envelope glycoprotein maturation. MuV, an enveloped RNA virus of the Paramyxoviridae family and an important human pathogen, enters the cell through the fusion of its envelope with the plasma membrane of the target cell. Membrane fusion is mediated by the viral attachment protein and the F protein. Cleavage of MuV-F into two subunits by furin is a prerequisite for fusion and virus infectivity. Here, we show that LAMPs support the furin-mediated cleavage of MuV-F. Expression levels of LAMPs affect the processing of MuV-F and MuV-mediated membrane fusion. Among LAMPs, the interferon-stimulated gene product LAMP3 is most critical in certain cells. Our study provides potential targets for anti-MuV therapeutics..
6. Yuta Shirogane, Takao Hashiguchi, Yusuke Yanagi, Weak cis and trans interactions of the hemagglutinin with receptors trigger fusion proteins of neuropathogenic measles virus isolates, Journal of virology, 10.1128/JVI.01727-19, 94, 2, 2020.01, [URL], Measles virus (MeV) is an enveloped RNA virus bearing two envelope glycoproteins, the hemagglutinin (H) and fusion (F) proteins. Upon receptor binding, the H protein triggers conformational changes of the F protein, causing membrane fusion and subsequent virus entry. MeV may persist in the brain, infecting neurons and causing fatal subacute sclerosing panencephalitis (SSPE). Since neurons do not express either of the MeV receptors, signaling lymphocytic activation molecule (SLAM; also called CD150) and nectin-4, how MeV propagates in neurons is unknown. Recent studies have shown that specific substitutions in the F protein found in MeV isolates from SSPE patients are critical for MeV neuropathogenicity by rendering the protein unstable and hyperfusogenic. Recombinant MeVs possessing the F proteins with such substitutions can spread in primary human neurons and in the brains of mice and hamsters and induce cell-cell fusion in cells lacking SLAM and nectin-4. Here, we show that receptor-blind mutant H proteins that have decreased binding affinities to receptors can support membrane fusion mediated by hyperfusogenic mutant F proteins, but not the wild-type F protein, in cells expressing the corresponding receptors. The results suggest that weak interactions of the H protein with certain molecules (putative neuron receptors) trigger hyperfusogenic F proteins in SSPE patients. Notably, where cell-cell contacts are ensured, the weak cis interaction of the H protein with SLAM on the same cell surface also could trigger hyperfusogenic F proteins. Some enveloped viruses may exploit such cis interactions with receptors to infect target cells, especially in cell-to-cell transmission. IMPORTANCE Measles virus (MeV) may persist in the brain, causing incurable subacute sclerosing panencephalitis (SSPE). Because neurons, the main target in SSPE, do not express receptors for wild-type (WT) MeV, how MeV propagates in the brain is a key question for the disease. Recent studies have demonstrated that specific substitutions in the MeV fusion (F) protein are critical for neuropathogenicity. Here, we show that weak cis and trans interactions of the MeV attachment protein with receptors that are not sufficient to trigger the WT MeV F protein can trigger the mutant F proteins from neuropathogenic MeV isolates. Our study not only provides an important clue to understand MeV neuropathogenicity but also reveals a novel viral strategy to expand cell tropism..
7. Shumpei Watanabe, Yuta Shirogane, Yuma Sato, Takao Hashiguchi, Yusuke Yanagi, New Insights into Measles Virus Brain Infections, Trends in Microbiology, 10.1016/j.tim.2018.08.010, 27, 2, 164-175, 2019.02, [URL], Measles virus (MeV) may persist in the brain, causing fatal neurodegenerative diseases, subacute sclerosing panencephalitis, and measles inclusion-body encephalitis. However, the mechanism of MeV propagation in the brain remains unexplained because human neurons affected by the diseases do not express the known receptors for MeV. Recent studies have revealed that certain changes in the ectodomain of the MeV fusion (F) protein play a key role in MeV spread in the brain. These changes destabilize the prefusion form of the F protein and render it hyperfusogenic, which in turn allows the virus to propagate in neurons. Based on crystal structures of the F protein, effective fusion inhibitors could be developed to treat these diseases..
8. Shumpei Watanabe, Yuta Shirogane, Satoshi Suzuki, Satoshi Ikegame, Ritsuko Koga, Yusuke Yanagi, Mutant Fusion Proteins with Enhanced Fusion Activity Promote Measles Virus Spread in Human Neuronal Cells and Brains of Suckling Hamsters, Journal of Virology, 10.1128/JVI.02632-12, 87, 5, 2648-2659, 2013.03, [URL], Subacute sclerosing panencephalitis (SSPE) is a fatal degenerative disease caused by persistent measles virus (MV) infection in the central nervous system (CNS). From the genetic study of MV isolates obtained from SSPE patients, it is thought that defects of the matrix (M) protein play a crucial role in MV pathogenicity in the CNS. In this study, we report several notable mutations in the extracellular domain of the MV fusion (F) protein, including those found in multiple SSPE strains. The F proteins with these mutations induced syncytium formation in cells lacking SLAM and nectin 4 (receptors used by wild-type MV), including human neuronal cell lines, when expressed together with the attachment protein hemagglutinin. Moreover, recombinant viruses with these mutations exhibited neurovirulence in suckling hamsters, unlike the parental wild-type MV, and the mortality correlated with their fusion activity. In contrast, the recombinant MV lacking the M protein did not induce syncytia in cells lacking SLAM and nectin 4, although it formed larger syncytia in cells with either of the receptors. Since human neuronal cells are mainly SLAM and nectin 4 negative, fusion-enhancing mutations in the extracellular domain of the F protein may greatly contribute to MV spread via cell-to-cell fusion in the CNS, regardless of defects of the M protein..
9. Mai Nakashima, Yuta Shirogane, Takao Hashiguchi, Yusuke Yanagi, Mutations in the putative dimer-dimer interfaces of the measles virus hemagglutinin head domain affect membrane fusion triggering, Journal of Biological Chemistry, 10.1074/jbc.M112.427609, 288, 12, 8085-8091, 2013.03, [URL], Measles virus (MV), an enveloped RNA virus belonging to the Paramyxoviridae family, enters the cell through membrane fusion mediated by two viral envelope proteins, an attachment protein hemagglutinin (H) and a fusion (F) protein. The crystal structure of the receptor-binding head domain of MV-H bound to its cellular receptor revealed that the MV-H head domain forms a tetrameric assembly (dimer of dimers), which occurs in two forms (forms I and II). In this study, we show that mutations in the putative dimer-dimer interface of the head domain in either form inhibit the ability of MV-H to support membrane fusion, without greatly affecting its cell surface expression, receptor binding, and interaction with the F protein. Notably, some anti-MV-H neutralizing monoclonal antibodies are directed to the region around the dimer-dimer interface in form I rather than receptor-binding sites. These observations suggest that the dimer-dimer interactions of the MV-H head domain, especially that in form I, contribute to triggering membrane fusion, and that conformational shift of head domain tetramers plays a role in the process. Furthermore, our results indicate that although the stalk and transmembrane regions may be mainly responsible for the tetramer formation of MV-H, the head domain alone can form tetramers, albeit at a low efficiency..
10. Yuta Shirogane, Shumpei Watanabe, Yusuke Yanagi, Cooperation between different RNA virus genomes produces a new phenotype, Nature Communications, 10.1038/ncomms2252, 3, 2012.12, [URL], An RNA virus population generally evolves rapidly under selection pressure, because of high error rates of the viral RNA polymerase. Measles virus, an enveloped RNA virus, has a fusion protein mediating fusion of the viral envelope with the cell membrane. Here we observe that a non-fusogenic recombinant measles virus evolves, after passages, into mutant viruses which regain the ability to induce membrane fusion. Unexpectedly, we identify a mutant virus possessing two types of genomes within a single virion: one genome encoding the wild-type fusion protein, the other a mutant version with a single amino-acid substitution. Neither the wild-type nor mutant protein by itself is able to mediate membrane fusion, but both together exhibit enhanced fusion activity through hetero-oligomer formation. Our results reveal a molecular mechanism for the 'cooperation' between different RNA virus genomes, which may have implications in viral evolution and in the evolution of other macromolecules..
11. Yuta Shirogane, Makoto Takeda, Maino Tahara, Satoshi Ikegame, Takanori Nakamura, Yusuke Yanagi, Epithelial-mesenchymal transition abolishes the susceptibility of polarized epithelial cell lines to measles virus, Journal of Biological Chemistry, 10.1074/jbc.M110.102590, 285, 27, 20882-20890, 2010.07, [URL], Measles virus (MV), an enveloped negative-strand RNA virus, remains a major cause of morbidity and mortality in developing countries. MV predominantly infects immune cells by using signaling lymphocyte activation molecule (SLAM; also called CD150) as a receptor, but it also infects polarized epithelial cells, forming tight junctions in a SLAM-independent manner. Although the ability of MV to infect polarized epithelial cells is thought to be important for its transmission, the epithelial cell receptor for MV has not been identified. A transcriptional repressor, Snail, induces epithelial-mesenchymal transition (EMT), in which epithelial cells lose epithelial cell phenotypes, such as adherens and tight junctions. In this study, EMTwas induced by expressing Snail in a lung adenocarcinoma cell line, II-18, which is highly susceptible to wild-type MV. Snail-expressing II-18 cells lost adherens and tight junctions. Microarray analysis confirmed the induction of EMT in II-18 cells and suggested a novel function of Snail in protein degradation and distribution. Importantly, wild-type MV no longer entered EMT-induced II-18 cells, suggesting that the epithelial cell receptor is down-regulated by the induction of EMT. Other polarized cell lines, NCI-H358 and HT-29, also lost susceptibility to wild-type MV when EMT was induced. However, the complete formation of tight junctions rather reduced MV entry into HT-29 cells. Taken together, these data suggest that the unidentified epithelial cell receptor forMVis involved in the formation of epithelial intercellular junctions..
12. Yuta Shirogane, Makoto Takeda, Masaharu Iwasaki, Nobuhisa Ishiguro, Hiroki Takeuchi, Yuichiro Nakatsu, Maino Tahara, Hideaki Kikuta, Yusuke Yanagi, Efficient multiplication of human metapneumovirus in vero cells expressing the transmembrane serine protease TMPRSS2, Journal of Virology, 10.1128/JVI.00676-08, 82, 17, 8942-8946, 2008.09, [URL], Human metapneumovirus (HMPV) is a major causative agent of severe bronchiolitis and pneumonia. Its fusion (F) protein must be cleaved by host proteases to cause membrane fusion, a critical step for virus infection. By generating Vero cells constitutively expressing the transmembrane serine protease TMPRSS2 and green fluorescent protein-expressing recombinant HMPV, we show that TMPRSS2, which is expressed in the human lung epithelium, cleaves the HMPV F protein efficiently and supports HMPV multiplication. The results indicate that TMPRSS2 is a possible candidate protease involved in the development of lower respiratory tract illness in HMPV-infected patients..
主要総説, 論評, 解説, 書評, 報告書等
1. 白銀 勇太、柳 雄介, 麻疹ウイルス受容体, 臨床とウイルス, 2019.03.
主要学会発表等
1. Ryuichi Takemoto, Tateki Suzuki, Takao Hashiguchi, Yusuke Yanagi, Yuta Shirogane, , Short-stalk isoforms of CADM1 and CADM2 induce membrane fusion mediated by hyperfusogenic fusion proteins of neuropathogenic measles viruses, 日本ウイルス学会学術集会, 2021.11, [Objectives]
Measles virus (MeV) may cause a progressive neurological disorder, subacute sclerosing panencephalitis (SSPE). MeV has the hemagglutinin (H) and fusion (F) proteins on its envelope. During viral entry, the H head domain binds to receptors, and then the H stalk domain transmits the fusion-triggering signal to the F. Recently, we have shown that cell adhesion molecule 1 (CADM1) and CADM2 are host factors enabling hyperfusogenic F protein (hF)-mediated membrane fusion by neuropathogenic MeVs. CADM1/2 interact in cis with the H on the same cell membrane, triggering membrane fusion. CADM1/2 exist in multiple splice isoforms containing various lengths of their stalks. This study investigated their differences in fusion-triggering, interaction with the H, and tissue distribution.
[Methods]
293FT cells were transfected with plasmids encoding H [the full length H, H(full), or the H lacking its head domain, H(headless), with or without a tetramerization domain (TD)], the hF, one of CADM1/2 isoforms, and EGFP, and observed under a fluorescence microscope 24-30 hours after transfection. Interactions of the isoforms with H were investigated by coimmunoprecipitation assay (Co-IP). Tissue distributions of the isoforms were obtained from the Genotype-Tissue Expression (GTEx) consortium using the GTEx Portal.
[Results]
Only short-stalk (SS) isoforms, which are predominantly expressed in the brain, induced syncytia, with either the H(full) or the H(headless)-TD. Co-IP showed that the SS isoforms interact with the H(headless), while long-stalk (LS) ones do not.
[Discussion]
These data suggest that structural changes in the CADM1/2 stalks might disrupt the essential site interacting with the H, or change their heights and make their binding sites apart from the corresponding binding site on the H. Notably, SS isoforms can interact in cis with the H(headless) and trigger fusion, independently of the H head domain. Thus, our results unveil a new mechanism of viral fusion triggering..
2. Yuta Shirogane, Ryuichi Takemoto, Tateki Suzuki, Tomonori Kameda, Kinichi Nakashima, Takao Hashiguchi, Yusuke Yanagi, Cell adhesion molecule (CADM) 1 and CADM2 enable measles virus spread in subacute sclerosing panencephalitis by cis-acting fusion triggering, 日本ウイルス学会学術集会, 2021.11, [Objectives]
Measles virus (MeV) may persist in the brain, causing subacute sclerosing panencephalitis (SSPE). MeV has the hemagglutinin (H) and fusion (F) proteins on its envelope. Upon receptor binding, the H triggers the F-mediated membrane fusion. Although MeV spreads in the brain by transsynaptic cell-to-cell fusion, neurons do not express the known receptors, signaling lymphocytic activation molecule family member 1 (SLAM) and nectin-4. We have recently shown that hyperfusogenic changes in the F enable MeV transmission between neurons. The structurally unstable hyperfusogenic F (hF) can be triggered even by the weak interaction between the SLAM/nectin-4-blind mutant H and its corresponding receptor. Here we investigated whether other SLAM/nectin family members, which may have structures closely related to the known receptors and weakly interact with the H, act as neuronal receptors.
[Methods]
Fusion-triggering by the SLAM/nectin family members, including CADM1/2, was evaluated by the dual split protein (DSP) assay as described previously (Shirogane et al., J Virol. 2020 Jan 6;94(2):e01727-19). Whether CADM1/2 act in trans (in cells different from those expressing the H and F) or in cis (in cells also expressing the H and F) was also examined. Interactions of CADM1/2 with H were investigated by coimmunoprecipitation (Co-IP). CADM1/2 knocked-down mouse primary neurons were infected with the recombinant MeV having hF, and the cells were observed under a fluorescence microscope 4 days after infection.
[Results]
The DSP assay and Co-IP showed that CADM1/2 interact in cis, but not in trans, with the H, triggering the hF-mediated membrane fusion. Knockdown of CADM1/2 inhibited neuropathogenic MeV transmission between mouse primary neurons.
[Discussion]
This study unravels the molecular mechanism by which MeV spreads transsynaptically between neurons, thereby causing SSPE. Careful screening may lead to more examples of such “cis-acting fusion triggering” in other viruses..
3. 白銀勇太、橋口隆生、柳雄介, 一般的な受容体の条件に制約されない麻疹ウイルスの低親和性受容体による膜融合の誘導, 日本分子生物学会, 2019.12, 麻疹ウイルスは脂質二重膜に被覆されたウイルス(エンベロープウイルス)の一種であり、エンベロープ上に受容体結合蛋白(H蛋白)と膜融合蛋白(F蛋白)を持つ。麻疹ウイルスの宿主受容体として免疫系細胞に発現するSLAM(CD150)および上皮系細胞に発現するNectin-4が同定されている。受容体はウイルス侵入時にH蛋白に結合し、続いてF蛋白の構造変化が誘導されてエンベロープと細胞膜が融合する。よって受容体はウイルスの接着と膜融合誘導という二つの機能を担う。また感染細胞に発現するH、F蛋白と隣接する細胞に発現する受容体の相互作用により細胞間の膜融合が引き起こされる。
麻疹ウイルスは稀ではあるが中枢神経に持続感染が成立し、シナプスを介して感染を拡大させ、致死性の亜急性硬化性全脳炎の原因となる。脳内環境に適応した麻疹ウイルスはF遺伝子が変異しており既知の受容体を持たない神経細胞で増殖可能となっている。これは変異により低親和性の宿主分子でも受容体として利用可能になるからだと予測されている。
私たちはこの仮説を証明するためH蛋白に既知の受容体(SLAMおよびNectin-4)との親和性を低下させる変異を導入し、低親和性受容体による膜融合誘導のための条件について検討を行った。その結果、麻疹ウイルスのF遺伝子に変異が入ることにより、1.H蛋白と親和性の低い受容体が細胞融合をトリガーできるようになること、2.低親和性受容体はH蛋白との接着能を失うが膜融合の誘導は可能なこと、3.膜融合の誘導はH蛋白と同一細胞に(cisに)受容体が発現しても起こり得ること、の3点を発見した。
神経細胞はシナプスで細胞同士が密に接しており、神経細胞間のウイルス伝搬は受容体による接着が必ずしも求められない。よって麻疹ウイルスは脳内に適応すると一般的な受容体の概念に縛られない増殖スタイルを確立していくと考えられる。本研究はウイルスの中枢神経病原性の分子メカニズムに迫るとともに、ウイルスの新たな進化可能性を提示する。
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4. Yuta Shirogane, Tateki Suzuki, Takao Hashiguchi, Ryuichi Takemoto, Yusuke Yanagi, A hyperfusogenic mutation in the measles virus fusion gene rescues the defect of receptor-blind mutations in the hemagglutinin gene, 日本ウイルス学会学術集会, 2019.10, [Objectives]
Measles virus (MV) is an enveloped RNA virus causing measles. MV has two envelope glycoproteins, the hemagglutinin (H) and fusion (F) protein. Upon binding to a host cell receptor, the H protein triggers the conformational changes of the F protein, resulting in membrane fusion. Two receptors for MV, signaling lymphocytic activation molecule (SLAM) and nectin-4, have been identified. In this study, we investigated whether a defect in one of the three steps of MV-mediated membrane fusion (the H protein-receptor interaction, F protein triggering by the H protein, and conformational changes of the F protein) can be compensated by a change in another step.
[Methods]
293FT cells were transfected with plasmids encoding the H, F, receptor, and EGFP genes to examine their fusogenicity. Plasmids encoding three types of H genes (wild-type H, SLAM-blind H(R533A), and nectin-4-blind H(Y543S)), plasmids encoding two types of F genes (wild-type F and F(T461I)), and plasmids encoding two receptors (SLAM and nectin-4), were used in different combinations.
[Results] Co-expression of wild-type H and wild-type F proteins with SLAM or nectin-4 induced syncytium formation. The H(R533A) and H(Y543S) mutant proteins did not support membrane fusion when expressed with SLAM and nectin-4, respectively. The F (T461I) protein has been shown to be destabilized and hyperfusogenic. When this mutant F protein was used, syncytium formation was clearly observed even in combination with H(R533A) and SLAM, or H(Y543S) and nectin-4. When the receptors were not expressed in cells, any combination of the H and F proteins did not induce syncytium formation.
[Discussion]
These data indicate that a hyperfusogenic mutation in the F protein could allow the H protein to utilize as its receptor a host molecule with a lower binding affinity than the authentic receptor. MVs derived from SSPE patients also have hyperfusogenic F proteins. Presumably, such mutations in the F protein could broaden the range of receptor usage and enable the viruses to spread in the brain tissues lacking known receptors..
学会活動
所属学会名
日本分子生物学会
日本ウイルス学会
学会大会・会議・シンポジウム等における役割
2018.10.28~2018.10.30, 日本ウイルス学会学術集会, 座長.
学術論文等の審査
年度 外国語雑誌査読論文数 日本語雑誌査読論文数 国際会議録査読論文数 国内会議録査読論文数 合計
2020年度      
研究資金
科学研究費補助金の採択状況(文部科学省、日本学術振興会)
2021年度~2022年度, 基盤研究(A), 分担, 中枢神経病原性ウイルスの新たな神経細胞伝播機構の解明.
2020年度~2022年度, 基盤研究(C), 代表, 麻疹ウイルスの進化が引き起こす亜急性硬化性全脳炎の発症機構の解明.
2018年度~2019年度, 研究活動スタート支援, 代表, 異種ウイルス間の干渉メカニズムの解明.
2015年度~2016年度, 研究活動スタート支援, 代表, ヒト病原性RNAウイルスのゲノム間協調がウイルス生存に果たす役割に関する研究.
競争的資金(受託研究を含む)の採択状況
2022年度~2022年度, 化血研若手研究奨励助成, 代表, 新概念「受容体模倣シス膜融合誘導」による麻疹ウイルス中枢神経病原メカニズムの解明.
学内資金・基金等への採択状況
2019年度~2019年度, Qdai-jump Research Program, 代表, 麻疹ウイルス進化による亜急性硬化性全脳炎の発症機構の解明.

九大関連コンテンツ

pure2017年10月2日から、「九州大学研究者情報」を補完するデータベースとして、Elsevier社の「Pure」による研究業績の公開を開始しました。
 
 
九州大学知的財産本部「九州大学Seeds集」