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• Graph and Hypergraph Theories Applied to Dynamic Protein-Protein Interaction Network Analysis, and Deep-Learning Frameworks for Protein Complex Network Prediction.

  Kai-Yu Chan, Tatsuo Yamaguchi, Yoshihiro Izumiya, Yen-Wei Chu, Tadashi Watanabe

  International journal of molecular sciences   27 ( 11 )   2026年05月 [ 査読有り ]

  掲載種別: 研究論文（学術雑誌）

  　概要を見る

  Protein interactions form large-scale networks known as protein-protein interaction networks (PPINs) or protein complex networks (PCNs). Extracting meaningful structural frameworks from these molecular relationships through mathematical modeling enables a deeper understanding of biological processes. Although static protein network models have provided valuable insights into the organization of PPINs, they are limited in their ability to capture the dynamic and cooperative nature of protein complexes. This review begins by introducing fundamental concepts in graph and hypergraph theory, with an emphasis on centrality measures. We then discuss the evolution of PPIN analysis from static representations to dynamic graph- and hypergraph-based frameworks. Specifically, we review dynamic PPINs and the challenges associated with their interpolation, dynamic centrality measures, and network models capable of representing multi-node relationships that have been applied to PPINs. Finally, we highlight recent advances in machine learning and deep learning approaches that integrate interaction data with functional annotations, sequence information, and cellular context to predict novel interactions and reconstruct transient protein complexes. Taken together, dynamic PPIN modeling combined with experimental validation provides an integrated framework for understanding coordinated protein functions in cellular processes and across biological systems as well as supporting drug development.

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• A LANA peptide inhibits tumor growth by inducing CHD4 protein cleavage and triggers cell death.

  Hiroki Miura, Kang-Hsin Wang, Tomoki Inagaki, Frank Chuang, Michiko Shimoda, Chie Izumiya, Tadashi Watanabe, Ryan R Davis, Clifford G Tepper, Somayeh Komaki, Ken-Ichi Nakajima, Ashish Kumar, Yoshihiro Izumiya

  Cell chemical biology     2024年10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) establishes a latent infection, and viral genes are poised to be transcribed in the latent chromatin. In the poised chromatins, KSHV latency-associated nuclear antigen (LANA) interacts with cellular chromodomain-helicase-DNA-binding protein 4 (CHD4) and inhibits viral promoter activation. CHD4 is known to regulate cell differentiation by preventing enhancers from activating promoters. Here, we identified a putative CHD4 inhibitor peptide (VGN73) from the LANA sequence corresponding to the LANA-CHD4 interaction surface. The VGN73 interacts with CHD4 at its PHD domain with a dissociation constant (KD) of 14 nM. Pre-treatment with VGN73 enhanced monocyte differentiation into macrophages and globally altered the repertoire of activated genes in U937 cells. Furthermore, the introduction of the peptide into the cancer cells induced caspase-mediated CHD4 cleavage, triggered cell death, and inhibited tumor growth in a xenograft mouse model. The VGN73 may facilitate cell differentiation therapy.

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• Conserved cysteine residues in Kaposi's sarcoma herpesvirus ORF34 are necessary for viral production and viral pre-initiation complex formation.

  Tadashi Watanabe, Aidan McGraw, Kedhar Narayan, Hasset Tibebe, Kazushi Kuriyama, Mayu Nishimura, Taisuke Izumi, Masahiro Fujimuro, Shinji Ohno

  Journal of virology     e0100024   2024年07月 [ 査読有り ]

  掲載種別: 研究論文（学術雑誌）

  　概要を見る

  UNLABELLED: Kaposi's sarcoma herpesvirus (KSHV) ORF34 plays a significant role as a component of the viral pre-initiation complex (vPIC), which is indispensable for late gene expression across beta- and gammaherpesviruses. Although the key role of ORF34 within the vPIC and its function as a hub protein have been recognized, further clarification regarding its specific contribution to vPIC functionality and interactions with other components is required. This study employed a deep learning algorithm-assisted structural model of ORF34, revealing highly conserved amino acid residues across human beta- and gammaherpesviruses localized in structured domains. Thus, we engineered ORF34 alanine-scanning mutants by substituting conserved residues with alanine. These mutants were evaluated for their ability to interact with other vPIC factors and restore viral production in cells harboring the ORF34-deficient KSHV-BAC. Our experimental results highlight the crucial role of the four cysteine residues conserved in ORF34: a tetrahedral arrangement consisting of a pair of C-Xn-C consensus motifs. This suggests the potential incorporation of metal cations in interacting with ORF24 and ORF66 vPIC components, facilitating late gene transcription, and promoting overall virus production by capturing metal cations. In summary, our findings underline the essential role of conserved cysteines in KSHV ORF34 for effective vPIC assembly and viral replication, thereby enhancing our understanding of the complex interplay between the vPIC components. IMPORTANCE: The initiation of late gene transcription is universally conserved across the beta- and gammaherpesvirus families. This process employs a viral pre-initiation complex (vPIC), which is analogous to a cellular PIC. Although KSHV ORF34 is a critical factor for viral replication and is a component of the vPIC, the specifics of vPIC formation and the essential domains crucial for its function remain unclear. Structural predictions suggest that the four conserved cysteines (C170, C175, C256, and C259) form a tetrahedron that coordinates the metal cation. We investigated the role of these conserved amino acids in interactions with other vPIC components, late gene expression, and virus production to demonstrate for the first time that these cysteines are pivotal for such functions. This discovery not only deepens our comprehensive understanding of ORF34 and vPIC dynamics but also lays the groundwork for more detailed studies on herpesvirus replication mechanisms in future research.

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• Analysis of the interaction between the ORF42 and ORF55 proteins encoded by Kaposi’s sarcoma-associated herpesvirus

  Kazushi Kuriyama, Tadashi Watanabe, Shinji Ohno

  Archives of Virology ( Springer Science and Business Media LLC )  169 ( 5 )   2024年04月 [ 査読有り ]

  掲載種別: 研究論文（学術雑誌）

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• Sofosbuvir Suppresses the Genome Replication of DENV1 in Human Hepatic Huh7 Cells

  Madoka Kurosawa, Fumihiro Kato, Takayuki Hishiki, Saori Ito, Hiroki Fujisawa, Tatsuo Yamaguchi, Misato Moriguchi, Kohei Hosokawa, Tadashi Watanabe, Noriko Saito-Tarashima, Noriaki Minakawa, Masahiro Fujimuro

  International Journal of Molecular Sciences ( MDPI AG )  25 ( 4 ) 2022 - 2022   2024年02月 [ 査読有り ]

  掲載種別: 研究論文（学術雑誌）

  　概要を見る

  Dengue virus (DENV) causes dengue fever and dengue hemorrhagic fever, and DENV infection kills 20,000 people annually worldwide. Therefore, the development of anti-DENV drugs is urgently needed. Sofosbuvir (SOF) is an effective drug for HCV-related diseases, and its triphosphorylated metabolite inhibits viral RNA synthesis by the RNA-dependent RNA polymerase (RdRp) of HCV. (2′R)-2′-Deoxy-2′-fluoro-2′-methyluridine (FMeU) is the dephosphorylated metabolite produced from SOF. The effects of SOF and FMeU on DENV1 replication were analyzed using two DENV1 replicon-based methods that we previously established. First, a replicon-harboring cell assay showed that DENV1 replicon replication in human hepatic Huh7 cells was decreased by SOF but not by FMeU. Second, a transient replicon assay showed that DENV1 replicon replication in Huh7 cells was decreased by SOF; however, in hamster kidney BHK-21 cells, it was not suppressed by SOF. Additionally, the replicon replication in Huh7 and BHK-21 cells was not affected by FMeU. Moreover, we assessed the effects of SOF on infectious DENV1 production. SOF suppressed infectious DENV1 production in Huh7 cells but not in monkey kidney Vero cells. To examine the substrate recognition of the HCV and DENV1 RdRps, the complex conformation of SOF-containing DENV1 RdRp or HCV RdRp was predicted using AlphaFold 2. These results indicate that SOF may be used as a treatment for DENV1 infection.

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• 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

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• [Replication Machinery of Kaposi's Sarcoma-associated Herpesvirus and Drug Discovery Research].

  Watanabe T, Fujimuro M

  Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan ( 公益社団法人 日本薬学会 )  139 ( 1 ) 69 - 73   2019年  [査読有り]

   

  DOI PubMed

• [Mechanisms of HIV replication and anti-HIV drug action].

  Koyanagi Y, Watanabe T

  Nihon rinsho. Japanese journal of clinical medicine   68 ( 3 ) 378 - 81   2010年03月  [査読有り]

   

  PubMed

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• 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

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• 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

   

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