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

PLoS Pathogens

Naoki Yamamoto¹  Hirotaka Ebina²  Youichi Suzuki²  Koji Ichiyama²  Yoshio Koyanagi²  Subhash G. Vasudevan²  Tatsuya Sawasaki²  Ching Hua Lee²  Toshifumi Matsuyama²  Qi'En Han²  Takayuki Hishiki²  Zhi Wen Eyo²  Kouichi Sano³  Wei-Xin Chin³  Kenji Ohba⁴  Yee-Joo Tan⁵  Hirotaka Takahashi⁵  Chikako Takahashi⁶  Justin Jang Hann Chu⁶  Beng Hui Tan⁶ 

[1] Department of Microbiology and Infection Control, Osaka Medical College, Takatsuki, Japan;Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore;Emerging Infectious Disease Program, Duke-NUS Graduate Medical School, Singapore;Laboratory of Primate Model, Experimental Research Center for Infectious Diseases, Institute for Virus Research, Kyoto University, Kyoto, Japan;Laboratory of Viral Pathogenesis, Institute for Virus Research, Kyoto University, Kyoto, Japan;Proteo-Science Center, Ehime University, Matsuyama, Japan

关键词: Small interfering RNAs;    Viral replication;    3' UTR;    RNA synthesis;    Protein translation;    Dengue virus;    Transfection;    Interferons;   

DOI  :  10.1371/journal.ppat.1005357

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY