Abstract
Dengue virus (DENV) disruption of the innate immune response is critical to establish infection. DENV non-structural protein 5 (NS5) plays a central role in this disruption, such as antagonism of STAT2. We recently found that DENV serotype 2 (DENV2) NS5 interacts with Polymerase associated factor 1 complex (PAF1C). The primary members of PAF1C are PAF1, LEO1, CTR9, and CDC73. This nuclear complex is an emerging player in the immune response. It promotes the expression of many genes, including genes related to the antiviral, antimicrobial and inflammatory responses, through close association with the chromatin of these genes. Our previous work demonstrated that NS5 antagonizes PAF1C recruitment to immune response genes. However, it remains unknown if NS5 antagonism of PAF1C is complementary to its antagonism of STAT2. Here, we show that knockout of PAF1 enhances DENV2 infectious virion production. By comparing gene expression profiles in PAF1 and STAT2 knockout cells, we find that PAF1 is necessary to express immune response genes that are STAT2-independent. Finally, we mapped the viral determinants for the NS5-PAF1C protein interaction. We found that NS5 nuclear localization and the C-terminal region of the methyltransferase domain are required for its interaction with PAF1C. Mutation of these regions rescued the expression of PAF1-dependent immune response genes that are antagonized by NS5. In sum, our results support a role for PAF1C in restricting DENV2 replication that NS5 antagonizes through its protein interaction with PAF1C.
Highlights
Dengue virus (DENV) is a major source of human disease and is responsible for nearly 400 million infections annually [1]
We recently found that DENV serotype 2 (DENV2) non-structural protein 5 (NS5) interacts with Polymerase associated factor 1 complex (PAF1C)
We previously showed that PAF1C restricts DENV2 replication by quantifying DENV antigen-positive cells by immunofluorescence microscopy [14]
Summary
Dengue virus (DENV) is a major source of human disease and is responsible for nearly 400 million infections annually [1]. DENV belongs to the Flavivirus genus of viruses, which are positive sense, capped single-stranded RNA viruses that rely on multifunctional proteins to replicate. In addition to playing a central role in genome replication, NS5 is a key player in disabling the innate immune response during DENV infection. Host protein interactions with NS5 are critical to its role in immune evasion. DENV NS5 binds human STAT2 and targets it for ubiquitin-mediated proteasomal degradation. This inhibits the expression of interferon-stimulated genes (ISGs) through interferon type 1 (IFN-I) signaling [6]
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