MYC-induced reprogramming of glutamine catabolism supports optimal virus replication

Minh Thai, Shivani K. Thaker, Jun Feng, Yushen Du, Hailiang Hu, Ting Ting Wu, Thomas G. Graeber, Daniel Braas and Heather R. Christofk ()
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Minh Thai: David Geffen School of Medicine, University of California
Shivani K. Thaker: David Geffen School of Medicine, University of California
Jun Feng: David Geffen School of Medicine, University of California
Yushen Du: David Geffen School of Medicine, University of California
Hailiang Hu: David Geffen School of Medicine, UCLA
Ting Ting Wu: David Geffen School of Medicine, University of California
Thomas G. Graeber: David Geffen School of Medicine, University of California
Daniel Braas: David Geffen School of Medicine, University of California
Heather R. Christofk: David Geffen School of Medicine, University of California

Nature Communications, 2015, vol. 6, issue 1, 1-9

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms9873

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