Viral growth factor- and STAT3 signaling-dependent elevation of the TCA cycle intermediate levels during vaccinia virus infection

Abstract

Metabolism is a crucial frontier of host-virus interaction as viruses rely on their host cells to provide nutrients and energy for propagation. Vaccinia virus (VACV) is the prototype poxvirus. It makes intensive demands for energy and macromolecules in order to build hundreds and thousands of viral particles in a single cell within hours of infection. Our comprehensive metabolic profiling reveals profound reprogramming of cellular metabolism by VACV infection, including increased levels of the intermediates of the tri-carboxylic acid (TCA) cycle independent of glutaminolysis. By investigating the level of citrate, the first metabolite of the TCA cycle, we demonstrate that the elevation of citrate depends on VACV-encoded viral growth factor (VGF), a viral homolog of cellular epidermal growth factor. Further, the upregulation of citrate is dependent on STAT3 signaling, which is activated non-canonically at the serine727 upon VACV infection. The STAT3 activation is dependent on VGF, and VGF-dependent EGFR and MAPK signaling. Together our study reveals a novel mechanism by which VACV manipulates cellular metabolism through a specific viral factor and by selectively activating a series of cellular signaling pathways.

A poxvirus decapping enzyme localizes to mitochondria to regulate RNA metabolism and translation, and promote viral replication

“…Western blot was performed as described previously [58]. Briefly, the samples were resolved by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), followed by transferring to a polyvinylidene difluoride membrane (PVDF).…”

The Role of Tricarboxylic Acid Cycle Metabolites in Viral Infections

“…The vaccinia virus for instance, encodes a viral homolog of the epidermal growth factor called viral growth factor which binds to the epithelial growth factor receptor, activates MAPK signaling and phosphorylates the signal transducer and activator of transcription 3 (STAT3) at the non-canonical site serine727. In this way vaccinia virus induces a 3.3-fold increase in the production of citrate and other TCA cycle metabolic intermediates at 8 h post infection ( Pant et al, 2021 ), thus contributing to fatty acid synthesis and protein acetylation. Since protein acetylation regulates enzyme activity, chromatin structure, protein localization, and protein-protein interaction ( Murray et al, 2018 ), the function of specific acetylated proteins and its impact on viral replication cycle remains to be analyzed.…”

Why do poxviruses still matter?

“…Research on these poxvirus gene functions will provide molecular tools to decipher aspects of cellular processes, in addition to understanding viral replication strategies. Work in the author's laboratory has recently focused on vaccinia virus factors that interact with host cell protein synthesis and metabolism machinery [51][52][53][54][55][56][57], with the rational that the study of virus interactions with these host housekeeping functions is critical to elucidate the poxvirus replication strategy and the associated fundamental cellular processes.…”