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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 U\n                    <jats:sub>L<\/jats:sub>\n                    38 protein modulate cellular metabolism and how these changes alter the response to nutrient limitation. We find that expression of U\n                    <jats:sub>L<\/jats:sub>\n                    38, either in the context of HCMV infection or in isolation, sensitizes cells to glucose limitation resulting in cell death. This sensitivity is mediated through U\n                    <jats:sub>L<\/jats:sub>\n                    38\u2019s inactivation of the TSC complex subunit 2 (TSC2) protein, a central metabolic regulator that possesses tumor-suppressive properties. Furthermore, expression of U\n                    <jats:sub>L<\/jats:sub>\n                    38 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.\n                  <\/jats:p>\n                  <jats:sec>\n                    <jats:title>IMPORTANCE<\/jats:title>\n                    <jats:p>\n                      Viruses modulate host cell metabolism to support the mass production of viral progeny. For human cytomegalovirus, we find that the viral U\n                      <jats:sub>L<\/jats:sub>\n                      38 protein is critical for driving these pro-viral metabolic changes. However, our results indicate that these changes come at a cost, as U\n                      <jats:sub>L<\/jats:sub>\n                      38 induces an anabolic rigidity that leads to a metabolic vulnerability. We find that U\n                      <jats:sub>L<\/jats:sub>\n                      38 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 U\n                      <jats:sub>L<\/jats:sub>\n                      38 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.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/mbio.03031-23","type":"journal-article","created":{"date-parts":[[2023,12,20]],"date-time":"2023-12-20T09:01:00Z","timestamp":1703062860000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":6,"title":["Cytomegalovirus-induced inactivation of TSC2 disrupts the coupling of fatty acid biosynthesis to glucose availability resulting in a vulnerability to glucose starvation"],"prefix":"10.1128","volume":"15","author":[{"given":"Matthew H.","family":"Raymonda","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Biophysics, School of Medicine and Dentistry, University of Rochester, Rochester, New York, USA"},{"name":"Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irene","family":"Rodr\u00edguez-S\u00e1nchez","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Rochester, Rochester, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xenia L.","family":"Schafer","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Biophysics, School of Medicine and Dentistry, University of Rochester, Rochester, New York, USA"},{"name":"Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leonid","family":"Smorodintsev-Schiller","sequence":"additional","affiliation":[{"name":"Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York, USA"},{"name":"Department of Biomedical Genetics, University of Rochester, Rochester, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isaac S.","family":"Harris","sequence":"additional","affiliation":[{"name":"Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York, USA"},{"name":"Department of Biomedical Genetics, University of Rochester, Rochester, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5379-9440","authenticated-orcid":true,"given":"Joshua","family":"Munger","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Biophysics, School of Medicine and Dentistry, University of Rochester, Rochester, New York, USA"},{"name":"Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York, USA"},{"name":"Department of Microbiology and Immunology, University of Rochester, Rochester, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tim.2015.08.007"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1556-4029.2009.01012.x"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.2146\/ajhp060379"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1517\/13543780802514195"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.7326\/0003-4819-118-3-199302010-00003"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1002\/cmdc.202100483"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1227919"},{"key":"e_1_3_3_9_2","volume-title":"Fields Virology","author":"Fields B","year":"2007","unstructured":"Fields B, Knipe D, Howley P, Griffin D. 2007. 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