2. Academic Validation
  3. Characterization of RyDEN (C19orf66) as an Interferon-Stimulated Cellular Inhibitor against Dengue Virus Replication

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

  • PLoS Pathog. 2016 Jan 6;12(1):e1005357. doi: 10.1371/journal.ppat.1005357.
Youichi Suzuki 1 2,  Wei-Xin Chin 1,  Qi'En Han 1,  Koji Ichiyama 1,  Ching Hua Lee 1,  Zhi Wen Eyo 1,  Hirotaka Ebina 3,  Hirotaka Takahashi 4,  Chikako Takahashi 4,  Beng Hui Tan 1,  Takayuki Hishiki 5,  Kenji Ohba 1,  Toshifumi Matsuyama 1,  Yoshio Koyanagi 3,  Yee-Joo Tan 1,  Tatsuya Sawasaki 4,  Justin Jang Hann Chu 1,  Subhash G Vasudevan 2,  Kouichi Sano 6,  Naoki Yamamoto 1
Affiliations

Affiliations

  • 1 Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
  • 2 Emerging Infectious Disease Program, Duke-NUS Graduate Medical School, Singapore.
  • 3 Laboratory of Viral Pathogenesis, Institute for Virus Research, Kyoto University, Kyoto, Japan.
  • 4 Proteo-Science Center, Ehime University, Matsuyama, Japan.
  • 5 Laboratory of Primate Model, Experimental Research Center for Infectious Diseases, Institute for Virus Research, Kyoto University, Kyoto, Japan.
  • 6 Department of Microbiology and Infection Control, Osaka Medical College, Takatsuki, Japan.
PMID: 26735137 DOI: 10.1371/journal.ppat.1005357
Abstract

Dengue virus (DENV) is one of the most important arthropod-borne pathogens that cause life-threatening diseases in humans. However, no vaccine or specific Antiviral is available for dengue. As seen in other RNA viruses, the innate immune system plays a key role in controlling DENV Infection and disease outcome. Although the interferon (IFN) response, which is central to host protective immunity, has been reported to limit DENV replication, the molecular details of how DENV Infection is modulated by IFN treatment are elusive. In this study, by employing a gain-of-function screen using a type I IFN-treated cell-derived cDNA library, we identified a previously uncharacterized gene, C19orf66, as an IFN-stimulated gene (ISG) that inhibits DENV replication, which we named Repressor of yield of DENV (RyDEN). Overexpression and gene knockdown experiments revealed that expression of RyDEN confers resistance to all serotypes of DENV in human cells. RyDEN expression also limited the replication of hepatitis C virus, Kunjin virus, Chikungunya virus, herpes simplex virus type 1, and human adenovirus. Importantly, RyDEN was considered to be a crucial effector molecule in the IFN-mediated anti-DENV response. When affinity purification-mass spectrometry analysis was performed, RyDEN was revealed to form a complex with cellular mRNA-binding proteins, poly(A)-binding protein cytoplasmic 1 (PABPC1), and La motif-related protein 1 (LARP1). Interestingly, PABPC1 and LARP1 were found to be positive modulators of DENV replication. Since RyDEN influenced intracellular events on DENV replication and, suppression of protein synthesis from DENV-based reporter construct RNA was also observed in RyDEN-expressing cells, our data suggest that RyDEN is likely to interfere with the translation of DENV via interaction with viral RNA and cellular mRNA-binding proteins, resulting in the inhibition of virus replication in infected cells.

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