Cytomegalovirus-induced inactivation of TSC2 disrupts the coupling of fatty acid biosynthesis to glucose availability resulting in a vulnerability to glucose starvation
ABSTRACTHuman cytomegalovirus (HCMV) modulates cellular metabolism to support productive infection, and the HCMV UL38 protein drives many aspects of this HCMV-induced metabolic program. However, it remains to be determined whether virally induced metabolic alterations might induce novel therapeutic...
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| Format: | Article |
| Language: | English |
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American Society for Microbiology
2024-01-01
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| Series: | mBio |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/mbio.03031-23 |
| _version_ | 1797353908674232320 |
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| author | Matthew H. Raymonda Irene Rodríguez-Sánchez Xenia L. Schafer Leonid Smorodintsev-Schiller Isaac S. Harris Joshua Munger |
| author_facet | Matthew H. Raymonda Irene Rodríguez-Sánchez Xenia L. Schafer Leonid Smorodintsev-Schiller Isaac S. Harris Joshua Munger |
| author_sort | Matthew H. Raymonda |
| collection | DOAJ |
| description | ABSTRACTHuman cytomegalovirus (HCMV) modulates cellular metabolism to support productive infection, and the HCMV UL38 protein drives many aspects of this HCMV-induced metabolic program. However, it remains to be determined whether virally induced metabolic alterations might induce novel therapeutic vulnerabilities in virally infected cells. Here, we explore how HCMV infection and the UL38 protein modulate cellular metabolism and how these changes alter the response to nutrient limitation. We find that expression of UL38, either in the context of HCMV infection or in isolation, sensitizes cells to glucose limitation resulting in cell death. This sensitivity is mediated through UL38’s inactivation of the TSC complex subunit 2 (TSC2) protein, a central metabolic regulator that possesses tumor-suppressive properties. Furthermore, expression of UL38 or the inactivation of TSC2 results in anabolic rigidity, in that the resulting increased levels of fatty acid biosynthesis are insensitive to glucose limitation. This failure to regulate fatty acid biosynthesis in response to glucose availability sensitizes cells to glucose limitation, resulting in cell death unless fatty acid biosynthesis is inhibited. These experiments identify a regulatory circuit between glycolysis and fatty acid biosynthesis that is critical for cell survival upon glucose limitation and highlight a metabolic vulnerability associated with viral infection and the inactivation of normal metabolic regulatory controls.IMPORTANCEViruses modulate host cell metabolism to support the mass production of viral progeny. For human cytomegalovirus, we find that the viral UL38 protein is critical for driving these pro-viral metabolic changes. However, our results indicate that these changes come at a cost, as UL38 induces an anabolic rigidity that leads to a metabolic vulnerability. We find that UL38 decouples the link between glucose availability and fatty acid biosynthetic activity. Normal cells respond to glucose limitation by down-regulating fatty acid biosynthesis. Expression of UL38 results in the inability to modulate fatty acid biosynthesis in response to glucose limitation, which results in cell death. We find this vulnerability in the context of viral infection, but this linkage between fatty acid biosynthesis, glucose availability, and cell death could have broader implications in other contexts or pathologies that rely on glycolytic remodeling, for example, oncogenesis. |
| first_indexed | 2024-03-08T13:37:44Z |
| format | Article |
| id | doaj.art-cbe99c7ea6ee460c98c222d77ae4b014 |
| institution | Directory Open Access Journal |
| issn | 2150-7511 |
| language | English |
| last_indexed | 2024-03-08T13:37:44Z |
| publishDate | 2024-01-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mBio |
| spelling | doaj.art-cbe99c7ea6ee460c98c222d77ae4b0142024-01-16T15:40:00ZengAmerican Society for MicrobiologymBio2150-75112024-01-0115110.1128/mbio.03031-23Cytomegalovirus-induced inactivation of TSC2 disrupts the coupling of fatty acid biosynthesis to glucose availability resulting in a vulnerability to glucose starvationMatthew H. Raymonda0Irene Rodríguez-Sánchez1Xenia L. Schafer2Leonid Smorodintsev-Schiller3Isaac S. Harris4Joshua Munger5Department of Biochemistry and Biophysics, School of Medicine and Dentistry, University of Rochester, Rochester, New York, USADepartment of Microbiology and Immunology, University of Rochester, Rochester, New York, USADepartment of Biochemistry and Biophysics, School of Medicine and Dentistry, University of Rochester, Rochester, New York, USAWilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York, USAWilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York, USADepartment of Biochemistry and Biophysics, School of Medicine and Dentistry, University of Rochester, Rochester, New York, USAABSTRACTHuman cytomegalovirus (HCMV) modulates cellular metabolism to support productive infection, and the HCMV UL38 protein drives many aspects of this HCMV-induced metabolic program. However, it remains to be determined whether virally induced metabolic alterations might induce novel therapeutic vulnerabilities in virally infected cells. Here, we explore how HCMV infection and the UL38 protein modulate cellular metabolism and how these changes alter the response to nutrient limitation. We find that expression of UL38, either in the context of HCMV infection or in isolation, sensitizes cells to glucose limitation resulting in cell death. This sensitivity is mediated through UL38’s inactivation of the TSC complex subunit 2 (TSC2) protein, a central metabolic regulator that possesses tumor-suppressive properties. Furthermore, expression of UL38 or the inactivation of TSC2 results in anabolic rigidity, in that the resulting increased levels of fatty acid biosynthesis are insensitive to glucose limitation. This failure to regulate fatty acid biosynthesis in response to glucose availability sensitizes cells to glucose limitation, resulting in cell death unless fatty acid biosynthesis is inhibited. These experiments identify a regulatory circuit between glycolysis and fatty acid biosynthesis that is critical for cell survival upon glucose limitation and highlight a metabolic vulnerability associated with viral infection and the inactivation of normal metabolic regulatory controls.IMPORTANCEViruses modulate host cell metabolism to support the mass production of viral progeny. For human cytomegalovirus, we find that the viral UL38 protein is critical for driving these pro-viral metabolic changes. However, our results indicate that these changes come at a cost, as UL38 induces an anabolic rigidity that leads to a metabolic vulnerability. We find that UL38 decouples the link between glucose availability and fatty acid biosynthetic activity. Normal cells respond to glucose limitation by down-regulating fatty acid biosynthesis. Expression of UL38 results in the inability to modulate fatty acid biosynthesis in response to glucose limitation, which results in cell death. We find this vulnerability in the context of viral infection, but this linkage between fatty acid biosynthesis, glucose availability, and cell death could have broader implications in other contexts or pathologies that rely on glycolytic remodeling, for example, oncogenesis.https://journals.asm.org/doi/10.1128/mbio.03031-23human cytomegalovirusUL38metabolismTSC2glycolysislipogenesis |
| spellingShingle | Matthew H. Raymonda Irene Rodríguez-Sánchez Xenia L. Schafer Leonid Smorodintsev-Schiller Isaac S. Harris Joshua Munger Cytomegalovirus-induced inactivation of TSC2 disrupts the coupling of fatty acid biosynthesis to glucose availability resulting in a vulnerability to glucose starvation mBio human cytomegalovirus UL38 metabolism TSC2 glycolysis lipogenesis |
| title | Cytomegalovirus-induced inactivation of TSC2 disrupts the coupling of fatty acid biosynthesis to glucose availability resulting in a vulnerability to glucose starvation |
| title_full | Cytomegalovirus-induced inactivation of TSC2 disrupts the coupling of fatty acid biosynthesis to glucose availability resulting in a vulnerability to glucose starvation |
| title_fullStr | Cytomegalovirus-induced inactivation of TSC2 disrupts the coupling of fatty acid biosynthesis to glucose availability resulting in a vulnerability to glucose starvation |
| title_full_unstemmed | Cytomegalovirus-induced inactivation of TSC2 disrupts the coupling of fatty acid biosynthesis to glucose availability resulting in a vulnerability to glucose starvation |
| title_short | Cytomegalovirus-induced inactivation of TSC2 disrupts the coupling of fatty acid biosynthesis to glucose availability resulting in a vulnerability to glucose starvation |
| title_sort | cytomegalovirus induced inactivation of tsc2 disrupts the coupling of fatty acid biosynthesis to glucose availability resulting in a vulnerability to glucose starvation |
| topic | human cytomegalovirus UL38 metabolism TSC2 glycolysis lipogenesis |
| url | https://journals.asm.org/doi/10.1128/mbio.03031-23 |
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