The Human Cytomegalovirus U(L)38 protein drives mTOR-independent metabolic flux reprogramming by inhibiting TSC2

Human Cytomegalovirus (HCMV) infection induces several metabolic activities that are essential for viral replication. Despite the important role that this metabolic modulation plays during infection, the viral mechanisms involved are largely unclear. We find that the HCMV U(L)38 protein is responsible for many aspects of HCMV-mediated metabolic activation, with U(L)38 being necessary and sufficient to drive glycolytic activation and induce the catabolism of specific amino acids. U(L)38’s metabolic reprogramming role is dependent on its interaction with TSC2, a tumor suppressor that inhibits mTOR signaling. Further, shRNA-mediated knockdown of TSC2 recapitulates the metabolic phenotypes associated with U(L)38 expression. Notably, we find that in many cases the metabolic flux activation associated with U(L)38 expression is largely independent of mTOR activity, as broad spectrum mTOR inhibition does not impact U(L)38-mediated induction of glycolysis, glutamine consumption, or the secretion of proline or alanine. In contrast, the induction of metabolite concentrations observed with U(L)38 expression are largely dependent on active mTOR. Collectively, our results indicate that the HCMV U(L)38 protein induces a pro-viral metabolic environment via inhibition of TSC2.