渡部 匡史 (ワタナベ タダシ)

WATANABE Tadashi

写真a

科研費研究者番号

60634326

出身大学 【 表示 / 非表示

  • 2001年04月
    -
    2005年03月

    北海道大学   薬学部   卒業

出身大学院 【 表示 / 非表示

  • 2005年04月
    -
    2007年03月

    北海道大学  薬学研究科  創薬化学専攻  博士前期課程  修了

  • 2007年04月
    -
    2011年03月

    京都大学  医学研究科  医学専攻  博士課程  単位取得満期退学

取得学位 【 表示 / 非表示

  • 京都大学 -  博士(医学)  ライフサイエンス / ウイルス学

職歴 【 表示 / 非表示

  • 2011年04月
    -
    2011年12月

      新潟市立 新潟市民病院 薬剤部 薬剤師  

  • 2012年01月
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    2015年03月

      京都薬科大学 助手  

  • 2015年04月
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    2020年03月

      京都薬科大学 助教  

  • 2020年04月
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    継続中

      琉球大学 医学研究科 講師  

所属学会・委員会 【 表示 / 非表示

  •  
     
     
     

    日本ウイルス学会

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    日本薬学会

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    日本分子生物学会

研究キーワード 【 表示 / 非表示

  • ウイルス学

研究分野 【 表示 / 非表示

  • ライフサイエンス / ウイルス学

  • ライフサイエンス / 薬系衛生、生物化学

  • ライフサイエンス / 感染症内科学

取得資格 【 表示 / 非表示

  • 薬剤師

論文 【 表示 / 非表示

  • The Contribution of Kaposi's Sarcoma-Associated Herpesvirus ORF7 and Its Zinc-Finger Motif to Viral Genome Cleavage and Capsid Formation.

    Yuki Iwaisako, Tadashi Watanabe, Manami Futo, Rimiko Okabe, Yuichi Sekine, Youichi Suzuki, Takashi Nakano, Masahiro Fujimuro

    Journal of virology     e0068422   2022年09月 [ 査読有り ]

    掲載種別: 研究論文(学術雑誌)

     概要を見る

    During Kaposi's sarcoma-associated herpesvirus (KSHV) lytic infection, lytic-related proteins are synthesized, viral genomes are replicated as a tandemly repeated form, and subsequently, capsids are assembled. The herpesvirus terminase complex is proposed to package an appropriate genome unit into an immature capsid, by cleavage of terminal repeats (TRs) flanking tandemly linked viral genomes. Although the mechanism of capsid formation in alpha- and betaherpesviruses are well-studied, in KSHV, it remains largely unknown. It has been proposed that KSHV ORF7 is a terminase subunit, and ORF7 harbors a zinc-finger motif, which is conserved among other herpesviral terminases. However, the biological significance of ORF7 is unknown. We previously reported that KSHV ORF17 is essential for the cleavage of inner scaffold proteins in capsid maturation, and ORF17 knockout (KO) induced capsid formation arrest between the procapsid and B-capsid stages. However, it remains unknown if ORF7-mediated viral DNA cleavage occurs before or after ORF17-mediated scaffold collapse. We analyzed the role of ORF7 during capsid formation using ORF7-KO-, ORF7&17-double-KO (DKO)-, and ORF7-zinc-finger motif mutant-KSHVs. We found that ORF7 acted after ORF17 in the capsid formation process, and ORF7-KO-KSHV produced incomplete capsids harboring nonspherical internal structures, which resembled soccer balls. This soccer ball-like capsid was formed after ORF17-mediated B-capsid formation. Moreover, ORF7-KO- and zinc-finger motif KO-KSHV failed to appropriately cleave the TR on replicated genome and had a defect in virion production. Interestingly, ORF17 function was also necessary for TR cleavage. Thus, our data revealed ORF7 contributes to terminase-mediated viral genome cleavage and capsid formation. IMPORTANCE In herpesviral capsid formation, the viral terminase complex cleaves the TR sites on newly synthesized tandemly repeating genomes and inserts an appropriate genomic unit into an immature capsid. Herpes simplex virus 1 (HSV-1) UL28 is a subunit of the terminase complex that cleaves the replicated viral genome. However, the physiological importance of the UL28 homolog, KSHV ORF7, remains poorly understood. Here, using several ORF7-deficient KSHVs, we found that ORF7 acted after ORF17-mediated scaffold collapse in the capsid maturation process. Moreover, ORF7 and its zinc-finger motif were essential for both cleavage of TR sites on the KSHV genome and virus production. ORF7-deficient KSHVs produced incomplete capsids that resembled a soccer ball. To our knowledge, this is the first report showing ORF7-KO-induced soccer ball-like capsids production and ORF7 function in the KSHV capsid assembly process. Our findings provide insights into the role of ORF7 in KSHV capsid formation.

  • Biomolecular Fluorescence Complementation Profiling and Artificial Intelligence Structure Prediction of the Kaposi's Sarcoma-Associated Herpesvirus ORF18 and ORF30 Interaction.

    Yoshiko Maeda, Tadashi Watanabe, Taisuke Izumi, Kazushi Kuriyama, Shinji Ohno, Masahiro Fujimuro

    International journal of molecular sciences   23 ( 17 )   2022年08月 [ 査読有り ]

    掲載種別: 研究論文(学術雑誌)

     概要を見る

    Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiologic agent of Kaposi's sarcoma, primary effusion lymphoma (PEL), and multicentric Castleman's disease. During KSHV lytic infection, lytic-related genes, categorized as immediate-early, early, and late genes, are expressed in a temporal manner. The transcription of late genes requires the virus-specific pre-initiation complex (vPIC), which consists of viral transcription factors. However, the protein-protein interactions of the vPIC factors have not been completely elucidated. KSHV ORF18 is one of the vPIC factors, and its interaction with other viral proteins has not been sufficiently revealed. In order to clarify these issues, we analyzed the interaction between ORF18 and another vPIC factor, ORF30, in living cells using the bimolecular fluorescence complementation (BiFC) assay. We identified four amino-acid residues (Leu29, Glu36, His41, and Trp170) of ORF18 that were responsible for its interaction with ORF30. Pull-down assays also showed that these four residues were required for the ORF18-ORF30 interaction. The artificial intelligence (AI) system AlphaFold2 predicted that the identified four residues are localized on the surface of ORF18 and are in proximity to each other. Thus, our AI-predicted model supports the importance of the four residues for binding ORF18 to ORF30. These results indicated that wet experiments in combination with AI may enhance the structural characterization of vPIC protein-protein interactions.

  • A comprehensive list of the Bunyavirales replication promoters reveals a unique promoter structure in Nairoviridae differing from other virus families.

    Yutaro Neriya, Shohei Kojima, Arata Sakiyama, Mai Kishimoto, Takao Iketani, Tadashi Watanabe, Yuichi Abe, Hiroshi Shimoda, Keisuke Nakagawa, Takaaki Koma, Yusuke Matsumoto

    Scientific reports   12 ( 1 ) 13560 - 13560   2022年08月 [ 査読有り ]

    掲載種別: 研究論文(学術雑誌)

     概要を見る

    Members of the order Bunyavirales infect a wide variety of host species, including plants, animals and humans, and pose a threat to public health. Major families in this order have tri-segmented negative-sense RNA genomes, the 5' and 3' ends of which form complementary strands that serve as a replication promoter. Elucidation of the mechanisms by which viral polymerases recognize the promoter to initiate RNA synthesis is important for understanding viral replication and pathogenesis, and developing antivirals. A list of replication promoter configuration patterns may provide details on the differences in the replication mechanisms among bunyaviruses. By using public sequence data of all known bunyavirus species, we constructed a comprehensive list of the replication promoters comprising 40 nucleotides in both the 5' and 3' ends of the genome that form a specific complementary strand. Among tri-segmented bunyaviruses, members of the family Nairoviridae, including the highly pathogenic Crimean-Congo hemorrhagic fever virus, have evolved a GC-rich promoter structure differing from that of other families. The unique promoter structure might be related to the large genome size of the family Nairoviridae among bunyaviruses, and the large genome architecture might confer pathogenic advantages. The promoter list provided in this report is useful for predicting the virus family-specific replication mechanisms of bunyaviruses.

  • A pyridinium‑type fullerene derivative suppresses primary effusion lymphoma cell viability via the downregulation of the Wnt signaling pathway through the destabilization of β‑catenin.

    Ayano Kadota, Misato Moriguchi, Tadashi Watanabe, Yuichi Sekine, Shigeo Nakamura, Takumi Yasuno, Tomoyuki Ohe, Tadahiko Mashino, Masahiro Fujimuro

    Oncology reports   47 ( 3 )   2022年03月 [ 査読有り ]

    掲載種別: 研究論文(学術雑誌)

     概要を見る

    Primary effusion lymphoma (PEL) is defined as a rare subtype of non‑Hodgkin's B cell lymphoma, which is caused by Kaposi's sarcoma‑associated herpesvirus (KSHV) in immunosuppressed patients. PEL is an aggressive type of lymphoma and is frequently resistant to conventional chemotherapeutics. Therefore, the discovery of novel drug candidates for the treatment of PEL is of utmost importance. In order to discover potential novel anti‑tumor compounds against PEL, the authors previously developed a pyrrolidinium‑type fullerene derivative, 1,1,1',1'‑tetramethyl [60]fullerenodipyrrolidinium diiodide (derivative #1), which induced the apoptosis of PEL cells via caspase‑9 activation. In the present study, the growth inhibitory effects of pyrrolidinium‑type (derivatives #1 and #2), pyridinium‑type (derivatives #3 and #5 to #9) and anilinium‑type fullerene derivatives (derivative #4) against PEL cells were evaluated. This analysis revealed a pyridinium‑type derivative (derivative #5; 3‑​5'‑(etho xycarbonyl)‑1',5'‑dihydro‑2'H‑[5,6]fullereno‑C60‑Ih‑[1,9‑c]pyrrol‑2'‑yl]‑1‑methylpyridinium iodide), which exhibited antitumor activity against PEL cells via the downregulation of Wnt/β‑catenin signaling. Derivative #5 suppressed the viability of KSHV‑infected PEL cells compared with KSHV‑uninfected B‑lymphoma cells. Furthermore, derivative #5 induced the destabilization of β‑catenin and suppressed β‑catenin‑TCF4 transcriptional activity in PEL cells. It is known that the constitutive activation of Wnt/β‑catenin signaling is essential for the growth of KSHV‑infected cells. The Wnt/β‑catenin activation in KSHV‑infected cells is mediated by KSHV latency‑associated nuclear antigen (LANA). The data demonstrated that derivative #5 increased β‑catenin phosphorylation, which resulted in β‑catenin polyubiquitination and subsequent degradation. Thus, derivative #5 overcame LANA‑mediated β‑catenin stabilization. Furthermore, the administration of derivative #5 suppressed the development of PEL cells in the ascites of SCID mice with tumor xenografts derived from PEL cells. On the whole, these findings provide evidence that the pyridinium‑type fullerene derivative #5 exhibits antitumor activity against PEL cells in vitro and in vivo. Thus, derivative #5 may be utilized as a novel therapeutic agent for the treatment of PEL.

  • Human hepatitis B virus-derived virus-like particle as a drug and DNA delivery carrier.

    Chiho Sakai, Kohei Hosokawa, Tadashi Watanabe, Youichi Suzuki, Takashi Nakano, Keiji Ueda, Masahiro Fujimuro

    Biochemical and biophysical research communications   581   103 - 109   2021年12月 [ 査読有り ]

    掲載種別: 研究論文(学術雑誌)

     概要を見る

    The controlled release of medications using nanoparticle-based drug delivery carriers is a promising method to increase the efficacy of pharmacotherapy and gene therapy. One critical issue that needs to be overcome with these drug delivery carriers is their target specificity. We focused on the cell tropism of a virus to solve this issue, i.e., we attempted to apply hepatitis B virus-like particle (HBV-VLP) as a novel hepatic cell-selective carrier for medication and DNA. To prepare HBV-VLP, 293T cells were transfected with expression plasmids carrying HBV envelope surface proteins, large envelope protein (L), and small envelope protein (S). After 72 h post-transfection, VLP-containing culture supernatants were harvested, and HBV-VLP was labeled with red fluorescent dye (DiI) and was purified by sucrose gradient ultracentrifugation. An anticancer drugs (geldanamycin or doxorubicin) and GFP-expressing plasmid DNA were incorporated into HBV-VLP, and medication- and plasmid DNA-loaded VLPs were prepared. We evaluated their delivery capabilities into hepatocytes, other organ-derived cells, and hepatocytes expressing sodium taurocholate cotransporting polypeptide (NTCP), which functions as the cellular receptor for HBV by binding to HBV L protein. HBV-VLP selectively delivered both anticancer drugs and plasmid DNA not into HepG2, Huh7, and other organ cells but into HepG2 cells expressing NTCP. In summary, we developed a novel delivery nanocarrier using HBV-VLP that could be used as a hepatitis selective drug- and DNA-carrier for cancer treatment and gene therapy.

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著書 【 表示 / 非表示

  • Human herpesviruses

    Tadashi Watanabe, Atsuko Sugimoto, Kouhei Hosokawa, Masahiro Fujimuro ( 担当: 分担執筆 , 担当範囲: Signal Transduction Pathways Associated with KSHV-Related Tumors )

    Springer Singapore  2018年 ( ページ数: viii, 501 p. )

  • EBウイルス 改訂第3版

    渡部匡史,藤室雅弘 ( 担当: 分担執筆 , 担当範囲: 1.ウイルスの構造と遺伝子  2)EBNA )

    診断と治療社  2015年09月

MISC(その他業績・査読無し論文等) 【 表示 / 非表示

論文査読・海外派遣等、研究諸活動 【 表示 / 非表示

  • Reviewer: Microbiology and Immunology (Japanese Society for Bacteriology, Japanese Society for Virology, Japanese Society for Host Defense Research)

    学術論文査読件数 

    2021年06月
    -
    継続中
     

  • Reviewer: Biological and Pharmaceutical Bulletin (Pharmaceutical Society of Japan)

    学術論文査読件数 

    2019年07月
    -
    継続中
     

  • Reviewer: Pharmacology (S. Karger AG, Medical and Scientific Publishers)

    学術論文査読件数 

    2017年10月
    -
    継続中
     

SDGs 【 表示 / 非表示

  • ウイルス複製機構の解明

担当授業科目(学内) 【 表示 / 非表示

  • 2020年度  ウイルス学実習  実験・実習・実技

  • 2020年度  ウイルス学  講義