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.
Highlights
Dengue virus (DENV) is a mosquito-borne virus belonging to the genus Flavivirus, which is a large family of enveloped, positive-stranded RNA viruses
Dengue virus (DENV), has immunologically distinct serotypes that increase the risk of life-threatening diseases such as dengue hemorrhagic fever
We have characterized C19orf66, named Repressor of yield of DENV (RyDEN), as a cellular gene that inhibits the replication of all DENV serotypes
Summary
Dengue virus (DENV) is a mosquito-borne virus belonging to the genus Flavivirus, which is a large family of enveloped, positive-stranded RNA viruses. While primary infection with one of the four DENV serotypes is often asymptomatic or causes self-limiting DF, due to the presence of non- or sub-neutralizing antibodies produced during the primary infection, a secondary infection with a different serotype increases the risk of a more severe form of dengue infection, such as life-threatening DHF and dengue shock syndrome (DSS). DENV infection begins with entry via receptor-mediated endocytosis, followed by particle disassembly to release an ~11-kb single-stranded RNA genome into the cytoplasm. The viral genomic RNA contains an open reading frame (ORF) encoding a single polyprotein, which is flanked by a capped 5’ untranslated region (UTR) and a non-polyadenylated 3’UTR, and serves as a template for the translation of a viral precursor protein. The structural proteins are used for the assembly of virus particles, while the NS proteins are mainly involved in synthesis of the viral RNA genome and the further translation process during DENV infection [2]
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