Journal
PLOS PATHOGENS
Volume 15, Issue 1, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.ppat.1007569
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Funding
- NIH [AI127370]
- American Cancer Society [RSG-15-049-01-MPC]
- American Heart Association
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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. Author summary Viruses are parasites that usurp the energy and molecular building blocks of their hosts to support their replication. In the past few years, numerous studies have shown that a wide variety of viruses induce cellular metabolic activities that are essential for successful infection. However, the viral mechanisms responsible for these metabolic alterations have remained unclear. Here, we find that the Human Cytomegalovirus (HCMV) U(L)38 gene is responsible for inducing many of the metabolic activities that are critical for successful HCMV infection. HCMV is a herpes virus that causes severe disease in newborns, as well as in those with weakened immune systems including transplant recipients and patients with common blood-based cancers. Our work shows that the U(L)38 protein drives cells to substantially increase the consumption of glucose and specific amino acids, which provide the energy and building blocks necessary to create new viral particles. Mechanistically, we find that U(L)38 triggers these metabolic changes through inhibition of a cellular tumor suppressor protein, TSC2. Collectively, our data provide substantial insight into how a viral pathogen reprograms cellular metabolism to support infection.
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