Adenovirus E4ORF1-induced MYC activation promotes host cell anabolic glucose metabolism and virus replication

Minh Thai; Nicholas A Graham; Daniel Braas; Michael Nehil; Evangelia Komisopoulou; Siavash K Kurdistani; Frank McCormick; Thomas G Graeber; Heather R Christofk

doi:10.1016/j.cmet.2014.03.009

Adenovirus E4ORF1-induced MYC activation promotes host cell anabolic glucose metabolism and virus replication

Cell Metab. 2014 Apr 1;19(4):694-701. doi: 10.1016/j.cmet.2014.03.009.

Authors

Minh Thai¹, Nicholas A Graham², Daniel Braas³, Michael Nehil⁴, Evangelia Komisopoulou², Siavash K Kurdistani⁵, Frank McCormick⁴, Thomas G Graeber⁶, Heather R Christofk⁷

Affiliations

¹ Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
² Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Crump Institute for Molecular Imaging, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
³ Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; UCLA Metabolomics Center, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁴ Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco School of Medicine, San Francisco, CA 94158, USA.
⁵ Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁶ Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Crump Institute for Molecular Imaging, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; UCLA Metabolomics Center, University of California, Los Angeles, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁷ Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; UCLA Metabolomics Center, University of California, Los Angeles, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: hchristofk@mednet.ucla.edu.

Abstract

Virus infections trigger metabolic changes in host cells that support the bioenergetic and biosynthetic demands of viral replication. Although recent studies have characterized virus-induced changes in host cell metabolism (Munger et al., 2008; Terry et al., 2012), the molecular mechanisms by which viruses reprogram cellular metabolism have remained elusive. Here, we show that the gene product of adenovirus E4ORF1 is necessary for adenovirus-induced upregulation of host cell glucose metabolism and sufficient to promote enhanced glycolysis in cultured epithelial cells by activation of MYC. E4ORF1 localizes to the nucleus, binds to MYC, and enhances MYC binding to glycolytic target genes, resulting in elevated expression of specific glycolytic enzymes. E4ORF1 activation of MYC promotes increased nucleotide biosynthesis from glucose intermediates and enables optimal adenovirus replication in primary lung epithelial cells. Our findings show how a viral protein exploits host cell machinery to reprogram cellular metabolism and promote optimal progeny virion generation.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adenovirus E4 Proteins / genetics
Adenovirus E4 Proteins / metabolism*
Cells, Cultured
Chromatin Immunoprecipitation
Epithelial Cells / metabolism*
Glucose / metabolism*
HeLa Cells
Humans
Immunoblotting
Immunoprecipitation
Metabolic Networks and Pathways / genetics
Metabolic Networks and Pathways / physiology*
Models, Biological*
Nucleotides / biosynthesis
Protein Binding
Proto-Oncogene Proteins c-myc / metabolism*
Virus Replication / genetics
Virus Replication / physiology*

Substances

Adenovirus E4 Proteins
MYC protein, human
Nucleotides
Proto-Oncogene Proteins c-myc
Glucose

Associated data

GEO/GSE52998

Abstract

Publication types

MeSH terms

Substances

Associated data

Grants and funding