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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Devito, Stefanie Renee Martínez-sobrido, Luis Ortiz-riaño, Emilio Munger, Joshua |
| Description | Author Affiliation: DeVito SR ( Departments of Biochemistry and Biophysics and.); Ortiz-Riaño E ( Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY 14642.); Martínez-Sobrido L ( Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY 14642.); Munger J ( Departments of Biochemistry and Biophysics and josh.munger@rochester.edu.); |
| Abstract | Human cytomegalovirus (HCMV) induces numerous changes to the host metabolic network that are critical for high-titer viral replication. We find that HCMV infection substantially induces de novo pyrimidine biosynthetic flux. This activation is important for HCMV replication because inhibition of pyrimidine biosynthetic enzymes substantially decreases the production of infectious virus, which can be rescued through medium supplementation with pyrimidine biosynthetic intermediates. Metabolomic analysis revealed that pyrimidine biosynthetic inhibition considerably reduces the levels of various UDP-sugar metabolites in HCMV-infected, but not mock-infected, cells. Further, UDP-sugar biosynthesis, which provides the sugar substrates required for glycosylation reactions, was found to be induced during HCMV infection. Pyrimidine biosynthetic inhibition also attenuated the glycosylation of the envelope glycoprotein B (gB). Both glycosylation of gB and viral growth were restored by medium supplementation with either UDP-sugar metabolites or pyrimidine precursors. These results indicate that HCMV drives de novo-synthesized pyrimidines to UDP-sugar biosynthesis to support virion protein glycosylation. The importance of this link between pyrimidine biosynthesis and UDP-sugars appears to be partially shared among diverse virus families, because UDP-sugar metabolites rescued the growth attenuation associated with pyrimidine biosynthetic inhibition during influenza A and vesicular stomatitis virus infection, but not murine hepatitis virus infection. In total, our results indicate that viruses can specifically modulate pyrimidine metabolic flux to provide the glycosyl subunits required for protein glycosylation and production of high titers of infectious progeny. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 50 |
| Volume Number | 111 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2014-12-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Cytomegalovirus Physiology Pyrimidines Biosynthesis Uridine Diphosphate Sugars Viral Envelope Proteins Metabolism Virus Replication Analysis Of Variance Chromatography, Liquid DNA Primers Genetics Glycosylation Metabolic Flux Analysis RNA Interference Real-Time Polymerase Chain Reaction Tandem Mass Spectrometry Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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