MYC-induced reprogramming of glutamine catabolism supports optimal virus replication

Abstract

Viruses rewire host cell glucose and glutamine metabolism to meet the bioenergetic and biosynthetic demands of viral propagation. However, the mechanism by which viruses reprogram glutamine metabolism and the metabolic fate of glutamine during adenovirus infection have remained elusive. Here, we show MYC activation is necessary for adenovirus-induced upregulation of host cell glutamine utilization and increased expression of glutamine transporters and glutamine catabolism enzymes. Adenovirus-induced MYC activation promotes increased glutamine uptake, increased use of glutamine in reductive carboxylation and increased use of glutamine in generating hexosamine pathway intermediates and specific amino acids. We identify glutaminase (GLS) as a critical enzyme for optimal adenovirus replication and demonstrate that GLS inhibition decreases replication of adenovirus, herpes simplex virus 1 and influenza A in cultured primary cells. Our findings show that adenovirus-induced reprogramming of glutamine metabolism through MYC activation promotes optimal progeny virion generation, and suggest that GLS inhibitors may be useful therapeutically to reduce replication of diverse viruses.

From Krebs to clinic: glutamine metabolism to cancer therapy

“…Glutamine in MYC-driven cells can be used for de novo proline synthesis 82 or production of the oncometabolite 2-hydroxyglutarate in breast cancer 152 , although the latter finding has not been independently corroborated. Infection by adenovirus or Kaposi’s sarcoma-associated herpesvirus (KSHV) both increase MYC expression and glutamine metabolism 153, 154 , and in the case of KSHV this may be a part of early tumorigenesis that eventually leads to Kaposi’s sarcoma. MYC can also mediate the reprogramming of glutamine metabolism downstream of activation of other oncogenic pathways, including mTOR 155 , and crosstalk with HER2 (also known as ERBB2) and the estrogen receptor (ER) in breast cancer 156 .…”

13C‐metabolic flux analysis of human adenovirus infection: Implications for viral vector production

“…Noteworthy, Thai et al () demonstrated that human adenovirus infection is associated with the upregulation of glycolytic enzymes through MYC activation, suggesting also an increase of glucose flux toward PPP metabolites. Additionally, a recent report extended this metabolic effect to elevated expression of glutamine transporters and glutamine catabolism enzymes (Thai et al, ). This points out that successful adenovirus infection induces a metabolic environment resembling that of cancer cells, echoing well known similarities between cancer cells and mammalian DNA viruses (Buchkovich et al, ; O'Shea et al, ), as well as the adenovirus oncogenic potential (Endter and Dobner, ; Georgakilas et al, ).…”

Hepatitis C virus infection triggers a tumor‐like glutamine metabolism

“…However, targeting GLS more specifically suppresses glutaminolysis, which strengthens the important role of this pathway in HCV replication. Interestingly, glutaminase inhibitors have recently also been shown to display antiviral activity against adenovirus, herpes simplex virus 1, and influenza A, suggesting that glutaminase inhibitors may be interesting to develop as general antivirals because they block the metabolic requirements for progeny virion production.…”