IFI16 is a Negative Regulator of Glucose and Cellular Lipid Metabolism during Human Cytomegalovirus Infection

Cellular lipid metabolism plays a pivotal role in human cytomegalovirus (HCMV) infection. Increased lipogenesis occurs upon HCMV infection most likely to favor the envelopment of newly synthesized particles. Here, we demonstrate that IFN-γ-inducible protein 16 (IFI16), previously characterized as a restriction factor of HCMV replication, interferes with metabolic pathways during infection. Specifically, we report that IFI16 hampers glucose uptake after HCMV infection by inhibiting the expression of the glucose transporter (GLUT) 4, resulting in decreased glucose consumption. GLUT4 downregulation is induced by a cooperation between IFI16 and the carbohydrate-response element-binding protein (ChREBP) on the GLUT4 promoter. Consequently, IFI16 reduces the transcription of the genes encoding lipogenic enzymes, leading to a decreased lipid synthesis and a reduced amount of enveloped viral particles in the infected cells. Finally, an untargeted lipidomic approach highlights the differences in lipid composition between WT and IFI16 KO cells particularly significantly increased cholesteryl esters content in IFI16 KO cells in comparison to WT cells. Overall, our data unravel a new role for IFI16 in the regulation of glucose and lipid metabolism upon HCMV replication and shed light for new promising targets in antiviral therapy.