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

Anil Pant,Zhilong Yang,Shuai Cao,Chen Peng,Lara Dsouza,Michael Lagunoff

doi:10.1371/journal.ppat.1009303

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.

Highlights

Viruses do not have metabolism and rely on their host cells for energy and molecular precursors to replicate
We show that Vaccinia virus (VACV) infection reprograms cellular metabolism globally, elevating the tri-carboxylic acid (TCA) cycle intermediate levels and modulating related cell metabolism
The elevation of the TCA cycle intermediates depends on the virus-encoded growth factor that stimulates non-canonical signal transducer and activator of transcription 3 (STAT3) signaling during VACV infection

Summary

Introduction

Viruses do not have metabolism and rely on their host cells for energy and molecular precursors to replicate. Vaccinia virus (VACV), the prototypic member of the poxviridae family, is a large, enveloped virus with a double-stranded DNA genome that encodes over 200 genes [4]. It had been used as the vaccine to eradicate smallpox, one of the deadliest diseases in human history [5]. VACV rewires host metabolism such that it upregulates glutamine metabolism [12,13] It depends on de novo fatty acid synthesis to generate an energy-favorable environment [14], suggesting the virus may need to modulate fatty acid synthesis. We have shown that VACV selectively upregulates the translation efficiency of oxidative phosphorylation (OXPHOS) mRNAs, indicating the requirement of increased and continuous supply of energy during virus replication [15]

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Discussion

Conclusion