title: 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.
authors.affiliation: Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, 90095 California, USA.
authors.forename: Minh
authors.initials: M
authors.lastname: Thai
authors.affiliation: Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, 90095 California, USA.
authors.forename: Shivani K
authors.initials: SK
authors.lastname: Thaker
authors.affiliation: Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, 90095 California, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Feng
authors.affiliation: Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, 90095 California, USA.
authors.forename: Yushen
authors.initials: Y
authors.lastname: Du
authors.affiliation: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, UCLA, Los Angeles, 90095 California, USA.|Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, Los Angeles, 90095 California, USA.
authors.forename: Hailiang
authors.initials: H
authors.lastname: Hu
authors.affiliation: Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, 90095 California, USA.
authors.forename: Ting
authors.initials: T
authors.lastname: Ting Wu
authors.affiliation: Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, 90095 California, USA.|Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, Los Angeles, 90095 California, USA.|Crump Institute for Molecular Imaging, David Geffen School of Medicine, University of California, Los Angeles, 90095 Californa, USA.|UCLA Metabolomics Center, Los Angeles, 90095 California, USA.
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Graeber
authors.affiliation: Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, 90095 California, USA.|Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, Los Angeles, 90095 California, USA.|Crump Institute for Molecular Imaging, David Geffen School of Medicine, University of California, Los Angeles, 90095 Californa, USA.|UCLA Metabolomics Center, Los Angeles, 90095 California, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Braas
authors.affiliation: Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, 90095 California, USA.|Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, Los Angeles, 90095 California, USA.|UCLA Metabolomics Center, Los Angeles, 90095 California, USA.|Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, 90095 California, USA.
authors.forename: Heather R
authors.initials: HR
authors.lastname: Christofk
mesh_terms: D000256:Adenoviridae / Q000502:physiology*; D002460:Cell Line; D005973:Glutamine / Q000378:metabolism*; D006801:Humans; D009154:Mutation; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D014779:Virus Replication / Q000502:physiology*
chemical_list: C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D005973:Glutamine