Characterization of RyDEN (C19orf66) as Interferon-Stimulated Cellular Inhibitor against Dengue Virus Replication

Youichi Suzuki, Wei-Xin Chin, Qi'En Han, Koji Ichiyama, Ching Hua Lee, Zhi Wen Eyo, Hirotaka Ebina, Hirotaka Takahashi, Chikako Takahashi, Beng Hui Tan, Takayuki Hishiki, Kenji Ohba, Toshifumi Matsuyama, Yoshio Koyanagi, Yee-Joo Tan, Tatsuya Sawasaki, Justin Jang Hann Chu, Subhash . Vasudevan, Kouichi Sano,Naoki Yamamoto

PLoS Pathogen. 2016 Jan 6;12(1):e1005357

Speaker: Po-Chun Chang (張博淳)                              Time: 14:00~15:00 May 11, 2016

Commentator: Dr. Yee-Shin Lin (林以行 老師)         Place: Room 601

Abstract:

        Dengue virus (DENV) is a positive-sense single-stranded RNA virus belonging to the family Flavivridae. It is known to cause serious diseases like dengue hemorrhagic fever (DHF). Unfortunately, no specific antiviral treatment is available for it. Innate immune system, substantially interferon (IFN) response plays a key role in virus defense. Although accumulated studies have indicated that DENV can inhibit IFN signaling to antagonize antiviral responses, cells pretreatment with IFNs has been shown to limit DENV replication. A previous study has revealed that at least 10 IFN-stimulated genes (ISGs) were potent cellular inhibitors of DENV replication, however, authors suggested that other non-identified ISGs may also participate in IFN-mediated auto-DENV response. In this study, authors executed a gain-of-function screen using a cDNA library derived from IFN-treated human cells to identify new cellular suppressive factors against DENV infection. C19orf66, a previously uncharacterized gene, which is named as repressor of yield of DENV (RyDEN) by authors, confers resistance to all serotypes of DENV in human cells thar are revealed by over-expression and gene knockdown experiments. Entry assay, luciferase reporter assay, and gene knockdown experiments further indicated that RyDEN is a crucial effector molecule in the IFN-mediated anti-DENV response which affects post-entry process of DENV replication. Affinity purification-mass spectrometry analysis results showed that RyDEN would form a complex with two cellular mRNA-binding protein, poly(A)-binding protein cytoplasmic 1 (PABPC1), and La motif-related protein 1 (LARP1). An earleir research has showed that PABP is able to bind the 3’UTR of DENV in vitro. By RNA-binding assay, RyDEN has showed to form complex with PABPC1, which specifies its binding ability to DENV RNA 3’UTR region. Despite, compared to the inhibition levels observed in DENV replication or viral RNA accumulation, translation inhibitory effect of RyDEN is relatively modest. Yet, RyDEN is considered to be suppressive to the translation process of DENV RNA. Some of other members of Flaviviridae and Togaviridae even some of DNA virus also are broadly susceptible to RyDEN. Collectively, RyDEN might be a candidate for development of antiviral drugs if we understand the detail mechanism of it.

Reference:

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