Cyclin-Dependent Kinases 8 and 19 Regulate Host Cell Metabolism during Dengue Virus Serotype 2 Infection

Abstract

Dengue virus infection is associated with the upregulation of metabolic pathways within infected cells. This effect is common to infection by a broad array of viruses. These metabolic changes, including increased glucose metabolism, oxidative phosphorylation and autophagy, support the demands of viral genome replication and infectious particle formation. The mechanisms by which these changes occur are known to be, in part, directed by viral nonstructural proteins that contact and control cellular structures and metabolic enzymes. We investigated the roles of host proteins with overarching control of metabolic processes, the transcriptional regulators, cyclin-dependent kinase 8 (CDK8) and its paralog, CDK19, as mediators of virally induced metabolic changes. Here, we show that expression of CDK8, but not CDK19, is increased during dengue virus infection in Huh7 human hepatocellular carcinoma cells, although both are required for efficient viral replication. Chemical inhibition of CDK8 and CDK19 with Senexin A during infection blocks virus-induced expression of select metabolic and autophagic genes, hexokinase 2 (HK2) and microtubule-associated protein 1 light chain 3 (LC3), and reduces viral genome replication and infectious particle production. The results further define the dependence of virus replication on increased metabolic capacity in target cells and identify CDK8 and CDK19 as master regulators of key metabolic genes. The common inhibition of CDK8 and CDK19 offers a host-directed therapeutic intervention that is unlikely to be overcome by viral evolution.

Identification of potential biomarkers in dengue via integrated bioinformatic analysis

“…Cell cycle, DNA replication, and protein processing were significantly enriched in KEGG pathway enrichment analysis, all of which are closely related to cell division. Knockdown of cyclin-dependent kinase 8/19-cyclinC (Cdk8/19-cyclin C) reduced genome replication of the dengue virus and mitochondrial function in infected and uninfected cells as well as weakened glucose metabolism and autophagy to inhibit viral replication and metabolism[ 46 ]. Cyclin G-associated kinases (GAK) phosphorylated adaptor protein complexes (APs), thereby regulating membrane transport and promoting the dengue virus infection[ 47 ].…”

Exploitation of the Mediator complex by viruses

“…Dengue virus enhancement of glucose metabolism and oxidative phosphorylation is well characterized [ 70 – 72 ]. Infection induces CDK8 expression, and CDK8 activity is required for the up-regulation of metabolic genes [ 73 ]. The dengue virus RNA-dependent RNA polymerase, NS5, has high affinity for host chromatin and associates with Med13 [ 73 , 74 ] (personal communication, R. Perera).…”

“…Infection induces CDK8 expression, and CDK8 activity is required for the up-regulation of metabolic genes [ 73 ]. The dengue virus RNA-dependent RNA polymerase, NS5, has high affinity for host chromatin and associates with Med13 [ 73 , 74 ] (personal communication, R. Perera). NS5 also interacts with spliceosomes to dysregulate splicing to favor virus replication and with polymerase associated factor 1 complex (PAF1C) to antagonize expression of PAF1-dependent immune response genes [ 75 , 76 ].…”

“…There are many cell signaling pathways, triggered by virus infection and replication, which would result in metabolic reprogramming without benefit of direct virus control of Mediator. However, as we move into a new era of Mediator control of nuclear condensates to stabilize transcription and splicing components in response to cell signaling [ 52 ], we may reconsider the roles of viral proteins such as NS5 that have high concentrations on active chromatin [ 73 , 74 ]. Whether they guide or enhance reprogramming, viral proteins will once again serve as models for for investigations of eukaryotic gene expression.…”

Role of glycolysis in myeloid cells during dengue infection

“…where glycolysis was crucial for maximal replication (330,331). CDK8 and CDK19 was found to be upregulated in DENV-infected Huh7 cells which subsequently increases HK2 expression (332). In addition, hypoxic environment increased replication of DENV in infected cells (333,334).…”