Upregulation of ATP Citrate Lyase Phosphorylation and Neutral Lipid Synthesis through Viral Growth Factor Signaling during Vaccinia Virus Infection

Abstract

Like all other viruses, poxviruses rely on host cells to provide metabolites and energy. Vaccinia virus (VACV), the prototype poxvirus, induces profound metabolic alterations in host cells. We previously showed that VACV infection increases the tricarboxylic acid (TCA) cycle intermediates, including citrate, that can be transported to the cytosol to be converted to acetyl-CoA for de novo fatty acid biosynthesis. ATP citrate lyase (ACLY) is a pivotal enzyme converting citrate to acetyl-CoA. Here, we report that VACV infection stimulates the S455 phosphorylation of ACLY, a post-translational modification that stimulates ACLY activity. We demonstrate that the chemical and genetic inhibition of ACLY severely suppresses VACV replication. Remarkably, we found that virus growth factor (VGF)- induced signaling is essential for the VACV-mediated upregulation of ACLY phosphorylation. Furthermore, the upregulation of ACLY phosphorylation during VACV infection is dependent on the activation of the cellular Akt kinase that phosphorylates ACLY. Finally, we report that VGF-induced ACLY phosphorylation via the EGFR-Akt pathway is important for VACV stimulations of neutral lipid droplet synthesis. These findings identified a previously unknown way of rewiring cell metabolism by a virus and a novel function for VGF in the governance of virus-host interactions through the induction of a key enzyme at the crossroads of the TCA cycle and fatty acid de novo biosynthesis. Our study also provides a mechanism for the role played by VGF and its downstream signaling cascades in the modulation of lipid metabolism in VACV-infected cells.

Role of vaccinia virus growth factor in stimulating the mTORC1-CAD axis of thede novopyrimidine pathway under different nutritional cues

“…An important, yet under studied aspect of poxvirus-host interactions, which limits the potential to develop new prevention and therapeutic strategies, is the modulation of key pathways that regulate host metabolism during poxvirus infection to produce the energy and metabolites necessary for viral replication 2 . We and others have previously reported that VACV actively alters host cell metabolism 20–23 . We demonstrated elegant mechanisms that identified the requirement of VGF to increase TCA cycle intermediates via STAT3 and reprograming of fatty acid metabolism upon VACV infection 21, 23 .…”

“…We and others have previously reported that VACV actively alters host cell metabolism 20–23 . We demonstrated elegant mechanisms that identified the requirement of VGF to increase TCA cycle intermediates via STAT3 and reprograming of fatty acid metabolism upon VACV infection 21, 23 . Another important aspect of metabolism is the realm of nucleotide metabolism as nucleotides serve as the building block for DNA and RNA synthesis 24 .…”